This chapter reviews social programs in the United States designed to minimize harms of psychoactive substance (drug) use, beginning with the Women’s Christian Temperance Union (WCTU) in the 1880s. This movement’s approach was based on fear-arousal, and targeted alcohol, marijuana, and other drugs. WCTU’s appeals were included in school textbooks and advanced the nationwide prohibition of alcohol (1920–1933). Prohibition’s end did not affect the US government’s use of lurid fear-based prevention communications introduced into school classrooms, which characterized prevention efforts for 40 years following prohibition’s end. The 1980s witnessed a shift to more benign approaches focused primarily on unqualified advice (e.g., “Just say no”), but dependence on fear arousal remained, and the approach was as unsuccessful as its predecessors. In the 1990s, the fear-based prevention model became less prominent, but ensuing campaigns produced an enormously costly and equally ineffective prevention campaign. The National Youth Anti-drug Media Campaign was a spectacular failure, whose demise was ensured by the premise that frequency of exposure alone would enhance attitude and behavior change. Disregarding the persuasive quality of media-based communications resulted in the campaign’s failure despite high exposure. More recent approaches involve smaller, more localized cooperative efforts of government with community organizations. These efforts, more attuned to local issues, broadened the scope of substances under consideration from marijuana to more potent drugs, perhaps owing to the “decriminalization” of the former substance in many states. These changes resulted in a virtual library of available prevention materials, which co-occurred with the rapid development of social media as a channel for prevention. Going forward, in its recent five-year plan, the US National Institute of Drug Abuse, the primary prevention organization in the United States, has responded with a five point plan that fosters development and test of novel prevention, treatment, harm reduction, and recovery support strategies. This plan promises to move from past failures to evidence-based approaches to meet the challenges of substance use today. The plan promises a hopeful new beginning that takes advantage of scientific knowledge to produce methods that succeed in this critical factor in the health of the society.