This paper conducts a review of the literature on acculturation by Latino adolescents to traditional European-American cultural values and its effect on their substance-using behaviors. This review includes a critical analysis of studies that examine the effects of acculturation on the mental wellbeing of Latino adolescents. Recent findings documenting the association between acculturation and substance use among Latino adolescents are discussed. This paper also examines the limitations of the current research and proposes the development of acculturation scales that focus on measuring the role that predominant Latino and American values, attitudes, and norms play in the substance-use behavior of Latino adolescents. Additionally, the author proposes the development of a conceptual framework that accounts for the impact of acculturation-related stress and the mitigating factors affecting such stress on the substance-use behavior of Latino adolescents. The author asserts that understanding the effects of acculturation-related stress and accompanying mitigating factors could begin to explain the increasingly high rates of substance use reported for Latino adolescents. There is a discussion of research gaps and related research issues, and recommendations for future research are also made.