The majority of youth with substance use disorders (SUDs) manifest one or more co-occurring psychiatric disorders. Consequently, many of these youths are being prescribed with psychotropic medications. As prescribing rates continue to increase for early-onset psychiatric disorders, potential risk for substance of abuse-psychiatric medication interactions may be enhanced. Because this type of drug-drug interaction has received little attention in the scientific literature, the authors conducted a systematic literature search examining the potential interactive adverse effects between psychotropic medications and substances of abuse in youth. Regardless of the scarcity of psychotropic medications-substance of abuse interactions found, it is important to stay vigilant due to the continued introduction of new classes of medications as well as the ever-changing map of street drugs. (Contains 1 table.)