Cocaine addiction in humans is characterized by persistent relapse vulnerability following detoxification. Relapse to drug taking can be precipitated by several factors: stress, re-exposure to drug-associated environmental cues, and re-exposure to the drug itself. Preclinical studies have focused on cocaine reinstatement, an animal model of relapse, to achieve a greater understanding of the underlying anatomical, neurobiological, and neurochemical bases of cocaine craving and relapse. Here, we review how changes in dopaminergic and glutamatergic transmission in mesocorticolimbic nuclei contribute to the reinstatement of cocaine seeking. This information can be used to elucidate which nuclei may prove effective therapeutic targets for deep brain stimulation (DBS) as a treatment for cocaine craving and relapse.