The persistance of addiction-associated cognitions and behavior is caused, in least part, by long-lasting drug-associated memories. Relapses, triggered by exposure to drug-associated cues, contribute considerably to the maintenance of addiction and are, even after drug-free periods for years, a major challenge in the treatment of addiction. An important advance in understanding the underlying pathophysiology derives from recent research results showing similarities between the process of drug addiction and physiological neural plasticity in learning and memory. In the focus of attention are basic mechanisms involving dopamine, glutamate, and their cellular and molecular targets leading to drug-induced synaptic alterations in the mesolimbic reward system. There is growing evidence from preclinical and clinical studies that specific treatments such as extinction training and cue-exposure therapy are effective. The challenge of future research is to determine which drug-induced adaptations are relevant to the pathophysiology of addiction and to generate more efficient therapies for extinction of addiction-associated cognitions and behavior.