Abstract; The disease process known as atherosclerosis is the leading cause of morbidity and mortality in the Western world. Current therapies have focused on treating the major risk factors identified to date including plasma lipid derangements, hypertension, clotting disorders, and diabetes. However, a significant number of individuals will be diagnosed with this malady in the apparent absence of known risk factors. Recent attention has turned toward treating the disease at the level of the vessel wall. 1n this review, we assess the relevancy of the oxygenating enzyme 15-lipoxygenase (15-LO) as a therapeutic target./;; vitro studies suggest that this enzyme may be involved in processes that modify native LDL in such a way as to be avidly taken up by tissue macrophages. 1n support of this contention are reports demonstrating the colocalization of 15-LO with macrophage-rich arterial lesions and epitopes of modified LDL. 1nvestigations using transgenic animals also suggest that the site of 15-LO expression may be an important factor in the development of the disease. The alteration of important cellular fatty acids may also generate intracellular signals that promote a pro-atherogenic phenotype in the absence of measurable changes in bulk lipid peroxidation. A limited number of studies have examined 15-LO inhibitors and those structural determinants necessary for inhibition of the enzyme. These include natural products and synthetic analogs. Structure activity relationships have been defined for a number of compounds including caffeic acid derivatives, propargyl ethers, and catechols. A novel, potent, specific inhibitor of 15-LO that lacks significant antioxidant activity was tested for its ability to inhibit atherosclerotic lesion formation in vivo. This benzothiopyranoindole virtually eliminated lesion formation in two animal models in the absence of significant changes in plasma lipids. Further, it prevented the progression of preestablished lesions in another study. Collectively, these data provide a strong scientific rationale for exploring the inhibition of 15-LO as a therapeutic strategy.