Depressive disorder rates in stimulant-dependent individuals are substantially higher than community rates. Further, depressive symptoms are considered a major component of stimulant withdrawal. The comorbidity of these disorders may reflect shared neurochemical alterations in the function of serotonin, dopamine, and peptide systems, such as corticotropin releasing factor (CRF) and neuropeptide Y (NPY). These alterations are observed in patients, and in animal models of depression and stimulant dependence, particularly in limbic brain structures. This shared neurobiology does not seem to result from significant shared heritability or genetic linkage; stimulants may induce changes in neurobiology that are similar to those found in depression, and these changes might provide a therapeutic target. Stimulant-dependent patients with a depressive disorder may be a specific subpopulation for antidepressant trials, and they might reduce their stimulant abuse when treated with antidepressants. Nevertheless, concomitant dependence on alcohol or opioids may influence this response, and antidepressants appear to be more effective for depression in combined stimulant and opioid dependence than in combined stimulant and alcohol dependence.