For over a decade, the Mexican government has invested itself in a “frontal attack” on drug trafficking organizations with catastrophic results. Little to nothing has been gained in limiting drug production, use, or trafficking, while violence has skyrocketed and major institutional and human rights crises have evolved. Through a multidisciplinary approach—which includes history, sociology, policy analysis, and constitutional doctrine—this essay evaluates drug prohibition in Mexico: its history, key components and documented results. It concludes that prohibition, as a guiding principle of drug policy, can and should be abandoned for all drugs, for both practical and normative reasons. It proposes a set of guiding principles that should orient the legalization of all drugs and then fleshes out concrete regulatory proposals for specific drug markets, pondering their relative benefits and risks. Although anchored in a specific case study, the essay should be considered a broader contribution to enrich discussions as drug policy reform moves from state to national jurisdictions and from marijuana to other drugs.