This article reviews the history of pharmacologic trials for the treatment of cocaine dependence as well as current treatments under investigation. The rationale for use of agents such as dopaminergic agents, antidepressants, and anticonvulsants is discussed. Early clinical trials with pharmacologic agents have demonstrated both positive and negative results; the possible reasons for these mixed outcomes is also discussed. Recent studies focusing on disulfiram, dopamine-selective antagonists, citicoline, aspirin, and a cocaine-specific vaccine are presented to highlight innovative and potentially effective treatments for individuals with cocaine dependence.