The problem of substance abuse impacts the Hispanic/Latino youth population. In some cases, subpopulations of the Hispanic/Latino population suffer higher rates of substance use than do other groups. While the science of prevention in the general population and the rigorous study of substances abuse prevention programs have flourished over the past few decades, there continues to be a limited body of knowledge regarding substance abuse prevention that is culturally specific or tailored to Hispanic/Latinos. One promising area is the study of risk and protective factors which finds that acculturation stress, among others, plays a key role in the development of substance use and other behavioral problems among youth. Stress experiences related to discrimination, immigration, parent–child cultural differences all play a role in disrupting normative development and subsequent risk-taking behavior. Culturally focused prevention models such as Familia Adelante show promise in helping reduce acculturation-based risk and increasing individual and family resilience. This chapter will address many of the aforementioned issues and will provide direction for future prevention research for Hispanic/Latinos.