Addiction to alcohol, tobacco, and illicit drugs of abuse continues to be one of the most significant medical, social, and economic problems facing our society. Since the mid-1960s, addictions have been recognized as diseases. We have hypothesized that three domains of factors contribute to the development and persistence of addictions: inherited or genetic differences in individual physiology, alterations in physiology induced by drugs or alcohol, and environmental or developmental factors. Neurochemical alterations in the brain caused by addictive drugs have a cellular and molecular basis and, in the setting of repeated self-exposure, which can lead to addiction, these changes may be persistent or even permanent. Such altered molecular, cellular, and neurophysiological "set points" in the brain, in turn, contribute to alterations in behavior with implications for the specific addictive diseases.