Illicit drug use by adolescents is an old problem with new clinical challenges, as teens access synthetic drugs in schools, on the street, and through internet purchase. Detection of synthetic drugs and unknown adulterants is often impossible using standard drug screens, but may be identified with the assistance of regional poison centers and the forensic laboratories of local universities and law enforcement, including the Drug Enforcement Agency. While clinical care for most intoxication and overdose cases is still largely supportive, critical interventions may be necessary for some. Toxicology experts at poison centers not only provide management advice contemporaneous to care, but compile data to identify local dangerous drug activity. This article reviews current knowledge of synthetic cannabinoids, amphetamines, and opioids, as well as the increasing teen use of “vaping” devices for delivery of tobacco and other substances.