Epidemiological and clinical data indicate high comorbidity between depression and drug dependence that may reflect an attempt to self-medicate with drugs of abuse. The present review examines whether these two psychiatric disorders are related by attempting to identify similarities in the neurobiology of depression and drug dependence. Emphasis is put on the neuromechanisms that may mediate specific core symptoms of both disorders that reflect alterations in reward and motivational processes. First, the epidemiological and clinical data on the comorbidity of the two disorders are reviewed briefly. Then, the neuroadaptations associated with psychomotor stimulant, opiate, ethanol, nicotine, and benzodiazepine dependence in animals are reviewed. Finally, the neurotransmitter systems whose function appears to be altered in depression (i.e., serotonin, norepinephrine, acetylcholine, dopamine, gamma-aminobutyric acid, corticotropin releasing factor, neuropeptide Y, and somatostatin), as revealed primarily by animal studies, are discussed. It is concluded that drug dependence and depression may be associated with alterations in some of the same neurotransmitter systems and, in particular, with alterations of neurotransmitter function in limbic-related brain structures. Thus, these two psychiatric disorders may be linked by some shared neurobiology. Nevertheless, it remains unclear whether drug abuse and depression are different symptomatic expressions of the same preexisting neurobiological abnormalities, or whether repeated drug abuse leads to the abnormalities mediating depression (i.e., drug-induced depressions). The hypothesis of self-medication of non-drug- and drug-induced depressions with drugs of abuse is also discussed as a potentially important explanatory concept in understanding the observed clinical comorbidity of these two psychiatric disorders.