The terrorist events of September 11th and the recent criminal anthrax exposures have increased awareness of the use of smallpox as a biological weapon. A shortage of the vaccine and the incidence of vaccine-related deaths will preclude protection of everyone especially immunocompromised patients. Currently, there are no FDA approved drugs for the treatment of smallpox. Recent literature has suggested that rifampicin, cidofovir, and virazole (ribavirin) are effective against smallpox; all, however, have logistical and medical complications that preclude their effective use. Thus, more effective and safer drugs will be required to combat smallpox in those exposed. Due to diverse microenvironments, oceans and seas contain a wealth of microorganisms that are genetically different from their terrestrial counterparts and represent a new avenue for isolating unique anti-viral therapeutics. The overall goal of this Phase I application is to identify and purify compounds from marine microorganisms that are bioactive against Vaccinia virus (VV). In Phase II, we will conduct in vitro studies with the purified compound, including a detailed evaluation of mechanisms of action. The goal for Phase II is to have a unique compound effective against VV ready for filing with an IND with the FDA, conducting the necessary in vivo clinical trials and initiating the stockpiling of anti-smallpox therapeutics as a preemptive anti-bioterrorism measure in a Phase III commercialization effort. Keywords: Smallpox, Bioterrorism, Therapeutics, Vaccinia, Antiviral Drugs, Marine Microorganisms. Potential Commercial application: The development of unique and cost-effective anti-smallpox drugs from a readily fermentable marine microorganism resource will be of tremendous benefit to the biosecurity of the United States. Such drugs may also become commercially important against other natural and emerging viral threats.