Research on adolescent use of substances has long sought to understand the family factors that may be associated with use of different substances such as alcohol, tobacco, and marijuana. However, scant attention has been focused on these questions in Latin American contexts, despite growing concerns about substance use among Latin American youth. Using data from a sample of 866 Chilean youth, we examined the relationship of family and neighborhood factors with youth substance abuse. We found that in a Latin American context, access to substances is an important predictor of use, but that neighborhood effects differ for marijuana use as opposed to cigarettes or alcohol. Age of youth, family and peer relationships, and gender all play significant roles in substance use. The study findings provide additional evidence that the use of substances is complex, whereby individual, family, and community influences must be considered jointly to prevent or reduce substance use among adolescents.