The authors empirically studied the self-medication hypothesis of drug abuse by examining drug effects and motivation for drug use in 494 hospitalized drug abusers. Most patients reported that they used drugs in response to depressive symptoms and experienced mood elevation, regardless of their drug of choice. Drug use to relieve depressive symptoms was far more likely in men if they had major depression, but was equally common in women with and without major depression. Information regarding a history of self-medication may thus be more helpful in diagnosing major depression in men than in women. Difficulties in diagnosing psychiatric disorders in substance abusers are discussed, as are the limitations of obtaining retrospective data on drug-using behavior. The implications of these limitations on the generalizability of the findings are reviewed.