This study examines how substance use is associated with the health and safety of homeless youth using cross-sectional, self-report data from 285 homeless adolescents. Path models were used to examine concurrent relationships between youth's substance use and multiple aspects of their health and safety, including measures of psychological distress, housing risk and instability, and medical problems. Substance use was examined with both global (i.e., a composite of days of use across various drugs and alcohol) and specific (i.e., rates of use of specific drugs, injection drug use) measures. After controlling for demographic and historical variables, number of days of use was significantly related to psychological distress, whereas injection drug use was significantly related to housing risk. Examination of specific drugs revealed relationships between psychological distress and the use of alcohol, cocaine, and amphetamines, and a specific relationship between housing risk and the use of heroin. None of the measures of substance use was significantly related to youth's medical problems. Implications for interventions with homeless adolescents are discussed.