Criminologists have largely neglected the influence of acculturation in the etiology of Hispanic drug use and delinquency. This is somewhat surprising since a long line of research from several disciplines has consistently linked higher levels of acculturation to greater incidence of negative social, health, and behavioral outcomes. A major shortcoming of this extant literature, however, is its failure to consider the acculturation-drug use link within a particular explanatory framework. This study attempts to address this oversight by examining the acculturation-drug use relationship within the context of gang membership, drug availability, and susceptibility to peer influence. Using data from a sample of Mexican-American adolescents residing in the American Southwest, a series of regression equations were estimated exploring the relative effects of acculturation, gang membership, drug availability, and susceptibility to peer influence on drug use. Separate analyses were conducted on minor (e.g., alcohol, marijuana) and major (e.g., cocaine, heroin) drug use. Findings indicated that all study variables, except acculturation, were significantly related to drug use.