Runaway youths represent a neglected clinical group, and few studies have examined ethnicity differences within this population. Substance use, family functioning and related problem behaviors were examined in a sample of Hispanic and Anglo runaway youths with substance abuse diagnoses (N = 145). Youths, aged 12–17, were recruited from two urban, southwestern runaway shelters. Within single-parent families, Anglo youths reported more marijuana use, and, regardless of family constitution, reported more tobacco use than did Hispanic youths. Overall, Anglo youths reported more externalizing problems and more conflict tactics used in resolving disagreements with their primary caretaker while Hispanic youths reported higher depression and familism scores. Given the differences found between Hispanic and Anglo youths, the findings argue that culturally sensitive interventions for runaway youths and families are warranted.