State-of-the-art downstream interventions are generally successful for half of drug-abusing clients. But, only one in four abusers actually receives treatment. In the midstream, one setting (schools), one type of prevention ("one size fits all"), and a limited age-range focus (adolescence and preadolescence) have predominated. Accumulating evidence casts doubt on the effectiveness of widely disseminated school-based prevention approaches, although theory-based programs that emphasize skills training and adjunctive parent and neighborhood interventions fare better. Newer pursuits include intervening very early with higher risk children and expanding to primary health care settings and workplaces. Popular but unproven community approaches need more rigorous evaluation. Upstream national and state public policy and environmental interventions should be reexamined in light of their success for preventing tobacco and alcohol use.