Drug addiction is a compulsive behavioral abnormality. In spite of pharmacologic and psychosocial treatments to reduce or eliminate drug taking, addiction tends to persist over time. Preclinical and human observations have converged on the hypothesis that addiction represents the pathologic deterioration of neural processes that normally serve affective and cognitive functioning. The major elements of persistent compulsive drug use are hypothesized to be molecular and cellular mechanisms that underlie enduring changes in a number of forebrain circuits (involving the ventral striatum and prefrontal cortex) that receive input from midbrain dopamine neurons and are involved in affective and cognitive mechanisms, respectively. Here we review progress in identifying crucial elements useful in understanding the pathophysiology of the disease and its pharmacologic treatment. Pharmacologic targeting of K-opiate receptors, with their discrete distribution within the dopaminergic system(s), and thus different actions on dopaminoceptive areas, may provide beneficial effects at the affective and cognitive level.