Relapse is a major characteristic of drug addiction disorders and remains the primary problem for treatment. Recently, there has been hope that these disorders may be amenable to pharmacological treatments that have successfully treated other psychopathological disorders. Pharmacological approaches to drug abuse have tended to be guided by the primary drug used by the individual, though substitution has been the guiding principle in some instances, as in the case of methadone maintenance in opioid addiction. Alternatively, blockade or antagonism of the effects of the primary drug being abused has been tried, as in the case of using naltrexone to treat opioid or alcohol addiction. Though reportedly successful in some populations, it is not clear that these approaches effectively control craving for ‘highs’ or euphoric experiences or a return to drug use as a response to stressful life experiences. Recent experimental studies of the factors that induce craving and relapse to drug use in both humans and laboratory animals, such as drug-related cues, re-exposure to the drug itself, or exposure to stressful events, have shown that the effects of these different events are mediated by dissociable neurochemical circuitry. Another finding that emerges from these studies is that the motivation underlying drug seeking induced by events that precipitate relapse is intensified by the duration and amount of pre-exposure to a drug and the passage of time since withdrawal of the drug. One implication of such findings for the treatment of addiction is that whatever approach is taken, treatment will have to be multifaceted and maintained over an extended period of time after the initial termination of drug use.