For decades, the debate over the merits of ending drug prohibition has carried on with little consequence. The recent near success of a cannabis legalization initiative in California suggests that citizens and politicians alike are more receptive to calls for change. We review basic research on deterrence and prices as well as emerging evidence on the potential empirical consequences of various alternatives to full prohibition, including depenalization, tolerated home cultivation, prescription regimes for cannabis and heroin, and retail sales of cannabis in Dutch coffee shops. The results are encouraging for advocates of these specific reforms, but the cases are inadequate for addressing the potentially more dramatic effects of full-scale commercial markets. The fundamental dilemma is that full legalization will probably reduce average harm per use but increase total consumption; the net effect of these two changes is difficult to project.