There are many sources of reinforcement in the spectrum of cocaine dependence that contribute to the compulsive cocaine self-administration or loss of control of cocaine intake that constitutes the core of modern definitions of dependence. The development of withdrawal has long been considered an integral part of drug addiction but has lost its impact in the theorization of drug dependence because of new emphasis on the neurobiological substrates for the positive-reinforcing properties of drugs. The present treatise reviews the neurobiological substrates for the acute positive reinforcing effects of cocaine and what is beginning to be known about the neurobiological substrates of cocaine withdrawal. The concept of motivational or affective withdrawal is reintroduced, which reemphasizes opponent process theory as a model for the motivational effects of cocaine dependence. The same neural substrates hypothesized to be involved in the acute reinforcing properties of drugs (basal forebrain regions of nucleus accumbens and amygdala) are hypothesized to be altered during chronic drug treatment to produce the negative motivational states characterizing drug withdrawal. Within these brain regions, both the neurochemical system(s) on which the drug has its primary actions and other neurochemical systems may undergo adaptations to chronic presence of the drug. An understanding of the adaptations of the motivational systems of the brain accompanying cocaine dependence leads to important predictions not only about the etiology, treatment, and prevention of cocaine addiction but also about the vulnerability of these motivational systems in non-drug-induced psychopathology.