The very fact that apoptosis and nonsteroidal anti-inflammatory drugs (NSAIDs) can be linked in the same title should tell you that something unusual is happening. The image of NSAIDs among physicians is certainly discordant with that associated with cancer treatment, which usually involves administration of drugs with serious or even life-threatening toxicity. In contrast, the drugs discussed in this review, including selective cyclooxygenase-2 inhibitors, lipoxygenase inhibitors, and novel NSAID derivatives (eg, sulindac sulfone and R-flurbiprofen), offer the promise of oral, nontoxic agents able to control the progression of established prostate cancer and possibly to prevent the development of prostate cancer de novo. NSAIDs were initially developed to suppress inflammation and pain by inhibiting the production of prostaglandin E2 and its metabolites. At first glance, the fact that NSAIDs are active against prostate cancer in laboratory and clinical studies might suggest that prostaglandins play a pivotal role in prostate cancer biology. However, the story is much more complex than that. Although cyclooxygenase-mediated production of prostaglandins appears to play an important role in the biology of prostate cancer, the NSAIDs and derivatives with promising activity against prostate cancer manifest several mechanisms of action that can include direct inhibition of eicosanoid formation, indirect inhibition of eicosanoid formation by inhibiting expression of enzymes involved in eicosanoid synthesis, or by interfering with the function of cyclic guanosine monophosphate.