This safety study examined trends in the prevalence of over-the-counter, prescription, and illicit drugs identified by toxicology testing of fatally injured pilots between 1990 and 2012. Safety issue areas identified during the study include (1) enhancing the precautionary information about potentially impairing drugs and conditions provided to pilots; (2) improving information about active pilots without medical certificates; (3) enhancing communication among prescribers, pharmacists, and patients about the transportation safety risks associated with some drugs and medical conditions; (4) developing and publicizing additional Federal Aviation Administration policy regarding marijuana use; and (5) researching the relationship between drug use and accident risk.