Drug dependence is a chronically relapsing disorder that places an enormous strain on healthcare systems. For treatments to have long-term clinical value, they must address the causes of relapse. Corticotropin-releasing factor (CRF), a neuropeptide central to the stress response, may be one key to solving the relapse cycle. CRF is hypothesized to mediate the elevated anxiety and negative emotional states experienced during the development of dependence. This review summarizes existing data on changes in the CRF system produced by drugs of abuse and the function of CRF receptors in regulating behavioural responses to drugs of abuse, with an emphasis on drug dependence. Drug-induced changes in neuronal excitability throughout the limbic system, as well as the reversal of these neuroadaptations by CRF receptor antagonists, are also addressed. CRF receptor antagonists, by reducing the motivational effects of drug withdrawal and protracted abstinence, are proposed to be novel therapeutic targets for drug abuse and addiction.