Abstract: Imaging studies have revealed neurochemical and functional changes in the brains of drug-addicted subjects that provide new insights into the mechanisms underlying addiction. Neurochemical studies have shown that large and fast increases in dopamine are associated with the reinforcing effects of drugs of abuse, but also that after chronic drug abuse and during withdrawal, brain dopamine function is markedly decreased and these decreases are associated with dysfunction of prefrontal regions (including orbitofrontal cortex and cingulate gyrus). The changes in brain dopamine function are likely to result in decreased sensitivity to natural reinforcers since dopamine also mediates the reinforcing effects of natural reinforcers and on disruption of frontal cortical functions, such as inhibitory control and salience attribution. Functional imaging studies have shown that during drug intoxication, or during craving, these frontal regions become activated as part of a complex pattern that includes brain circuits involved with reward (nucleus accumbens), motivation (orbitofrontal cortex), memory (amygdala and hippocampus), and cognitive control (prefrontal cortex and cingulate gyrus). Here, we integrate these findings and propose a model that attempts to explain the loss of control and compulsive drug intake that characterize addiction. Specifically, we propose that in drug addiction the value of the drug and drug-related stimuli is enhanced at the expense of other reinforcers. This is a consequence of conditioned learning and of the resetting of reward thresholds as an adaptation to the high levels of stimulation induced by drugs of abuse. In this model, during exposure to the drug or drug-related cues, the memory of the expected reward results in overactivation of the reward and motivation circuits while decreasing the activity in the cognitive control circuit. This contributes to an inability to inhibit the drive to seek and consume the drug and results in compulsive drug intake. This model has implications for therapy, for it suggests a multi-prong approach that targets strategies to decrease the rewarding properties of drugs, to enhance the rewarding properties of alternative reinforcers, to interfere with conditioned-learned associations, and to strengthen cognitive control in the treatment of drug addiction.