Effective medications for cocaine dependence are needed to improve outcome in this chronic, relapsing disorder. Medications affecting glutamate function are reasonable candidates for investigation, given the involvement of glutamate circuits in reward-related brain regions and evidence of cocaine-induced glutamatergic dysregulation. In addition, it is increasingly apparent that glutamatergic mechanisms underlie several clinical aspects of cocaine dependence, including euphoria, withdrawal, craving, and hedonic dysfunction. Even denial, traditionally viewed as purely psychological, may result, in part, from dysfunctional glutamate-rich cortical regions. We review the involvement of glutamate in reward-related circuits, the acute and chronic effects of cocaine on these pathways, and glutamatergic mechanisms that contribute to the neurobiology of cocaine dependence. We also present preliminary data from our research of modafinil, a glutamate-enhancing agent with promise in the treatment of cocaine-addicted individuals.