OBJECTIVE Drugs of abuse have a significant impact on the stress responsive hypothalamic-pituitary-adrenal (HPA) axis and an abnormal response to stress may mediate the development or maintenance of addictive diseases. In animals, drugs of abuse, such as cocaine, lead to an activation of the HPA axis. Drugs of abuse also have an impact on the endogenous opioid system (EOS) and the dopaminergic system. Each of these systems has also been implicated in the mediation of aggressive behaviors. This brief report focuses on the effects of drugs of abuse on the stress responsive HPA, EOS and dopaminergic systems, and the role of these systems in mediating aggression and comorbidity of substance abuse and aggressive behaviors. METHODS Rodents were administered either 'binge' pattern cocaine (15 mg/kg x 3 each day) or the androgenic anabolic steroid nandrolone decanoate and the effects on mRNA levels, receptor binding and circulating levels of stress hormones were analyzed. RESULTS Both cocaine and nandrolone decanoate significantly impact the HPA axis, the EOS and the dopaminergic systems. CONCLUSIONS Drugs of abuse impact substantially the same neural systems that affect aggressive behavior.