Scientists have been aware of the existence of a complex relationship between stress and the subsequent activation of the hypothalamic-pituitary-adrenal (HPA) axis and the endocrine and neurobehavioral effects of cocaine for many years now. Our research program has focused on the involvement of HPA axis activation in cocaine reinforcement using the intravenous self-administration model. Behaviorally, there are at least three general phases in the etiology of drug self-administration to consider: acquisition, maintenance and reinstatement. We have investigated the role for the HPA axis during each of these three phases. Corticosterone is necessary during acquisition; self-administration does not occur unless this stress-related hormone is increased above a threshold critical for reward. Sensitivity to low doses of cocaine falling on the ascending limb of the acquisition dose-response curve can be augmented by increasing circulating levels of corticosterone, but similar treatments do not affect responding maintained by higher doses. In a similar vein, ongoing, low-dose cocaine self-administration is decreased by drugs affecting the synthesis and/or secretion of corticosterone. When higher doses falling on the descending limb of the cocaine dose-response curve are self-administered, plasma corticosterone can still reach this hypothetical reward threshold even when synthesis is inhibited, and drug intake is not affected. On the other hand, the self-administration of doses falling on both the ascending and descending limbs of the cocaine dose-response curve can each be attenuated by drugs that block central corticotropin-releasing hormone (CRH) receptors. Finally, corticosterone and CRH are also critical for the stress- and cue-induced reinstatement of extinguished cocaine-seeking behavior, demonstrating an involvement of the HPA axis in the relapse to cocaine use as well. Continued investigations into how stress and the subsequent activation of the HPA axis affect cocaine self-administration will likely result in the identification of more effective and efficient treatment for cocaine addiction.