Increasing our knowledge about the major addictive diseases, opiate and cocaine addiction and alcoholism, is of great importance from a public, as well as personal health perspective. Each disease is associated with profound and negative impacts on physical and mental health and also each has devastating social and economic consequences. Each of these addictive diseases has been associated with major infectious diseases including AIDS, hepatitis B, C, D and G, either through parenteral or sexual transmission. Since 1967, we have addressed the research question related to our early hypotheses on the development of an addiction, that atypical responsitivity to stress and stressors may play a central role in the acquisition and persistence of, and relapse to, drug abuse. We have been conducting studies both in humans and in animal models focused on the role of disruption of the stress responsive hypothalamic-pituitary-adrenal axis in opiate addiction, cocaine dependency and alcoholism. We also have conducted studies of the role of the endogenous opioid system in modulation of this axis, as well as the interaction of the endogenous opioid system with the dopaminergic system and other neurotransmitter and neuropeptides related to the reinforcing effects of drugs of abuse.