This study examined the role of family structure and functioning in predicting substance use among Hispanic/Latino adolescents, surveyed in 9th and 10th grade. The sample (N = 1433) was half female, mostly of Mexican descent, and the majority was born in the United States. Living with a single father was associated with less parental monitoring and less family cohesion (gamma = -0.07, -0.06, respectively). Living with a single mother was associated with less parental monitoring (gamma = -0.10). Living with neither parent was associated with less communication (gamma = -0.08), less parental monitoring (gamma = -0.09), more family conflict (gamma = 0.06), and less family cohesion (gamma = -0.06). Less monitoring was associated with substance use at follow-up (beta = -0.17). Low rates of parental monitoring appear to mediate the association between parental family structure and substance use. Results suggest that improving basic parenting skills and offering additional social support and resources to assist parents in monitoring adolescents may help prevent substance use. These interventions may be particularly beneficial for single parents.