<PAGE>   1
As filed with the Securities and Exchange Commission on June 1, 1998
Registration No. 333-
================================================================================


                       SECURITIES AND EXCHANGE COMMISSION
                             Washington, D.C. 20549


                                    FORM S-8
                             REGISTRATION STATEMENT
                                      UNDER
                           THE SECURITIES ACT OF 1933


                           ISIS PHARMACEUTICALS, INC.
             (Exact Name Of Registrant As Specified In Its Charter)



            DELAWARE                                    33-0336973
(State Or Other Jurisdiction Of             (I.R.S. Employer Identification No.)
 Incorporation Or Organization)


                               2292 FARADAY AVENUE
                           CARLSBAD, CALIFORNIA 92008
                    (Address Of Principal Executive Offices)



                             1989 STOCK OPTION PLAN
                            (Full Title Of The Plan)

                             B. LYNNE PARSHALL, ESQ.
         EXECUTIVE VICE PRESIDENT, CHIEF FINANCIAL OFFICER AND SECRETARY
                           ISIS PHARMACEUTICALS, INC.
                               2292 FARADAY AVENUE
                           CARLSBAD, CALIFORNIA 92008
                                 (760) 931-9200

       (Name, Address, Including Zip Code, And Telephone Number, Including
                        Area Code, Of Agent For Service)


                                   Copies to:

                              D. BRADLEY PECK, ESQ.
                               COOLEY GODWARD LLP
                        4365 EXECUTIVE DRIVE, SUITE 1100
                           SAN DIEGO, CALIFORNIA 92121
                                 (619) 550-6000




<PAGE>   2

                         CALCULATION OF REGISTRATION FEE


<TABLE>
<CAPTION>
                                                       PROPOSED MAXIMUM      PROPOSED MAXIMUM 
TITLE OF SECURITIES TO BE REGISTERED   AMOUNT TO BE    OFFERING PRICE PER       AGGREGATE               AMOUNT OF 
                                       REGISTERED         SHARE (1)          OFFERING PRICE (1)     REGISTRATION FEE
====================================================================================================================
<S>                                     <C>            <C>                   <C>                    <C>      
Stock Options and Common Stock (par
value $.001)
                                        2,000,000      $13.5625-$15.4375       $27,148,859             $8,008.91
====================================================================================================================
</TABLE>



(1) Estimated solely for the purpose of calculating the amount of the
registration fee pursuant to Rule 457(c) and (h)(1). The price per share and the
aggregate offering price are calculated on the basis of (a) the weighted average
of $14.4375 - $15.4375, the exercise price for 15,470 shares subject to
outstanding options granted under the Registrant's 1989 Stock Option Plan and
(b) $13.5625, the average of the high and low sales prices of Registrant's
Common Stock on May 27, 1998 as reported on the Nasdaq National Market.


================================================================================


<PAGE>   3

                    INCORPORATION BY REFERENCE OF CONTENTS OF
         REGISTRATION STATEMENT ON FORM S-8 NO. 33-42356, NO. 33-51236,
    NO. 33-54840, NO. 33-58450, NO. 33-75150, NO. 33-90780 AND NO. 333-05825


           The contents of Registration Statements on Form S-8 Nos. 33-42356,
33-51236, 33-54840, 33-58450, 33-75150, 33-90780 and 333-05825 filed with the
Securities and Exchange Commission on August 23, 1991, August 25, 1992, November
20, 1992, February 16, 1993, February 4, 1994, March 30, 1995 and June 12, 1996,
respectively, are incorporated by reference herein.

                                    EXHIBITS


<TABLE>
<CAPTION>
EXHIBIT
NUMBER
<S>     <C>                                  
5.1     Opinion of Cooley Godward LLP

23.1    Consent of Ernst & Young LLP

23.2    Consent of Cooley Godward LLP is contained in Exhibit 5.1 to this
        Registration Statement.

24.1    Power of Attorney is contained on the signature pages.

99.1*   1989 Stock Option Plan, as amended.
</TABLE>


- ----------------

*       Filed as an exhibit to the Registrant's Annual Report on Form 10-K for
        the year ended December 31, 1997, and incorporated herein by reference.



<PAGE>   4

                                   SIGNATURES


           Pursuant to the requirements of the Securities Act of 1933, as
amended, the Registrant certifies that it has reasonable grounds to believe that
it meets all of the requirements for filing on Form S-8 and has duly caused this
Registration Statement to be signed on its behalf by the undersigned, thereunto
duly authorized, in the City of Carlsbad, State of California, on May 22, 1998.


                                     ISIS PHARMACEUTICALS, INC.



                                     By /s/ B. LYNNE PARSHALL
                                        ----------------------------------------
                                            B. Lynne Parshall
                                            Executive Vice President, Chief 
                                            Financial Officer and Secretary
                                            (Principal Financial and Accounting
                                            Officer)


                                POWER OF ATTORNEY


           KNOW ALL PERSONS BY THESE PRESENTS, that each person whose signature
appears below constitutes and appoints Stanley T. Crooke, Daniel L. Kisner and
B. Lynne Parshall and each or any one of them, his or her true and lawful
attorney-in-fact and agent, with full power of substitution and resubstitution,
for him or her and in his or her name, place and stead, in any and all
capacities, to sign any and all amendments (including post-effective amendments)
to this Registration Statement, and to file the same, with all exhibits thereto,
and other documents in connection therewith, with the Securities and Exchange
Commission, granting unto said attorneys-in-fact and agents, and each of them,
full power and authority to do and perform each and every act and thing
requisite and necessary to be done in connection therewith, as fully to all
intents and purposes as he or she might or could do in person, hereby ratifying
and confirming all that said attorneys-in-fact and agents, or any of them, or
their or his or her substitutes or substitute, may lawfully do or cause to be
done by virtue hereof.

           Pursuant to the requirements of the Securities Act of 1933, this
Registration Statement has been signed by the following persons in the
capacities and on the dates indicated.


<TABLE>
<CAPTION>
SIGNATURE                             TITLE                                              DATE
- ---------                             -----                                              ----
<S>                                   <C>                                                <C>


/s/ STANLEY T. CROOKE                 Chairman of the Board and Chief Executive          May 22, 1998
- -----------------------------------   Officer (Principal Executive Officer)
Stanley T. Crooke                     


/s/ B. LYNNE PARSHALL                 Executive Vice President, Chief Financial          May 22, 1998
- -----------------------------------   Officer and Secretary (Principal Financial
B. Lynne Parshall                     and Accounting Officer)
                                      


/s/ DANIEL L. KISNER                  President, Chief Operating Officer and             May 22, 1998
- -----------------------------------   Director
Daniel L. Kisner                      
</TABLE>


                                       2.


<PAGE>   5


<TABLE>
<S>                                   <C>                                                <C> 
/s/ CHRISTOPHER F.O. GABRIELI         Director                                           May 22, 1998
- -----------------------------------
Christopher F.O. Gabrieli


/s/ BURKHART BLANK                    Director                                           May 22, 1998
- -----------------------------------
Burkhart Blank


/s/ ALAN C. MENDELSON                 Director                                           May 22, 1998
- -----------------------------------
Alan C. Mendelson


/s/ WILLIAM R. MILLER                 Director                                           May 22, 1998
- -----------------------------------
William R. Miller


/s/ MARK B. SKALETSKY                 Director                                           May 22, 1998
- -----------------------------------
Mark B. Skaletsky


/s/ LARRY SOLL                        Director                                           May 22, 1998
- -----------------------------------
Larry Soll


                                      Director                                           May 22, 1998
- -----------------------------------
Joseph H. Wender

</TABLE>


                                       3.


<PAGE>   6

                                  EXHIBIT INDEX



<TABLE>
<CAPTION>
EXHIBIT
NUMBER                                         DESCRIPTION                         SEQUENTIAL PAGE NUMBER
- ------                                         -----------                         ----------------------
<S>            <C>                                                                 <C>
 5.1           Opinion of Cooley Godward LLP                                                   7

23.1           Consent of Ernst & Young LLP                                                    8

23.2           Consent of Cooley Godward LLP is contained in Exhibit 5.1 
               to this Registration Statement

24.1           Power of Attorney is contained on the signature pages

99.1*          1989 Stock Option Plan, as amended                                             --

</TABLE>



*       Filed as an exhibit to the Registrant's Annual Report on Form 10-K for
        the year ended December 31, 1997, and incorporated herein by reference.







<PAGE>   1

                                                                     EXHIBIT 5.1

May 27, 1998

ISIS PHARMACEUTICALS, INC.
2292 Faraday Avenue
Carlsbad, CA  92008

Ladies and Gentlemen:

You have requested our opinion with respect to certain matters in connection
with the filing by Isis Pharmaceuticals, Inc. (the "Company") of a Registration
Statement on Form S-8 (the "Registration Statement") with the Securities and
Exchange Commission covering the offering of up to 2,000,000 shares of the
Company's Common Stock, $.001 par value pursuant to its 1989 Stock Option Plan
(the "Option Plan") (the "Shares").

In connection with this opinion, we have examined the Registration Statement and
related Prospectus, your Certificate of Incorporation and By-laws, as amended,
and such other documents, records, certificates, memoranda and other instruments
as we deem necessary as a basis for this opinion. We have assumed the
genuineness and authenticity of all documents submitted to us as originals, the
conformity to originals of all documents submitted to us as copies thereof, and
the due execution and delivery of all documents where due execution and delivery
are a prerequisite to the effectiveness thereof.

On the basis of the foregoing, and in reliance thereon, we are of the opinion
that the Shares,
 when sold and issued in accordance with the Option Plan, the
Registration Statement and related Prospectus, will be validly issued, fully
paid, and nonassessable.

We consent to the filing of this opinion as an exhibit to the Registration
Statement.

Very truly yours,

Cooley Godward LLP


By:/s/  L. KAY CHANDLER
   -------------------------------
           L. Kay Chandler





<PAGE>   1

                                                                    EXHIBIT 23.1


               CONSENT OF ERNST & YOUNG LLP, INDEPENDENT AUDITORS

We consent to the incorporation by reference in the Registration Statement (Form
S-8) pertaining to the 1989 Stock Option Plan of Isis Pharmaceuticals, Inc. for
the registration of 2,000,000 shares of common stock of our report dated January
23, 1998, except for the first and last paragraphs of Note 4, as to which the
date is February 27, 1998, with respect to the financial statements of Isis
Pharmaceuticals, Inc. included in its Annual Report (Form 10-K) for the year
ended December 31, 1997, filed with the Securities and Exchange Commission.


                                         ERNST & YOUNG LLP

San Diego, California
May 26, 1998