The role of statin therapy in prostate cancer (PCa) prevention and treatment is plagued by controversy. This critical review of published clinical series reveals several caveats in earlier studies, which reported no benefit. Recent studies that adjust for confounding factors have demonstrated statin therapy to be associated with PCa prevention and favorable clinical outcomes. Developed as inhibitors of cholesterol synthesis, the expected mechanism of statin action is systemic cholesterol reduction. By lowering circulating cholesterol, statins indirectly reduce cellular cholesterol levels in multiple cell types, impacting on membrane microdomains and steroidogenesis. Although non-cholesterol mechanisms of statin action have been proposed, they are limited by the uncertainties surrounding in vivo tissue statin concentrations.