Prostanoids and related arachidonic acid derivatives are important physiologic modulators in arteries, as well as mediators of inflammation, hemostasis, and cell proliferation. Their participation in atherosclerosis and in acute thrombotic events is complex, as demonstrated by untoward cardiovascular (CV) effects associated with clinical use of inhibitors of prostaglandin synthesis for treatment of chronic pain, inflammatory states, or cancer prophylaxis. Newer understanding of the pathophysiology of atherosclerosis and the pharmacology of prostanoids promises potential resolution of current problems resulting from the hazards of available prostanoid-altering drugs.