Homicide is the second leading cause of death for teens in the United States. Individual alcohol and drug use are important influences on teens’ risk of homicide. Yet, risk created by others around adolescents, in their families and neighbourhoods is unclear. The purpose of this study was to determine whether individual, family, or neighbourhood exposures to alcohol and other drugs each increase the risk of homicide. We conducted a population based case-control study including 162 homicide victims ages 13 to 20 years old and 176 matched controls living in Philadelphia over a 3 year period. Case data were collected from multiple sources: police, medical examiner and child death review team and others. Control data were collected using a random digit dial assessing alcohol and drug exposures. After adjusting, adolescents who were under the influence of an illegal substance at the time of the incident were 4.82 (p < 0.05) times more likely to be victims of homicide than those not under the influence. This was not the case for adolescents under the influence of alcohol. Both history of drug use (4.73, p < 0.05) and history of alcohol abuse (3.98, p < 0.05) significantly increased risk of homicide. Adolescents with caregivers who used drugs were much more likely to be victims of homicide (13.87, p < 0.01). Neighbourhood alcohol and drug exposures did not have a significant effect on risk of homicide in this study. Results from our study indicate that family and individual exposures are key risk factors for adolescent homicide, where associations between neighbourhood exposures and risk of homicide were not significant. Addressing individual and family exposure to drugs and alcohol is important to adolescent homicide prevention. While efforts may focus on individual drug and alcohol abuse, familial influences may pose a much greater risk, suggesting that the family environment should be a priority.