Drug addiction, as a disease, has grown to reach the level of a social illness. Psychostimulants, opiates, alcohol, nicotine and cannabis abuse affects millions worldwide and virtually all classes of modern society. In spite of the enormous proportions of its spread, intimate neurobiological mechanisms leading to distintictive features of this pathological status, such as craving for the abused substance and loss of control over intake, remain largely obscure and pharmacotherapies sadly unsatisfactory. In the last decade, preclinical and clinical research in this field has made great progress to improve our understanding of the brain mechanisms which form the basis of this illness. The review of recent literature, which represents the focus of the present paper, leads to the emerging consensus that an alteration of physiological mechanisms of neural plasticity within the brain dopamine and glutamate systems may underlie some of the behavioral abnormalities occurring during the dependence cycle. In particular, a reduction of dopamine neuronal activity and glutamate neurotransmission at the level of the ventrotegmental area, after withdrawal from chronic administration of drugs of abuse, may work in concert with alterations in other forebrain areas, such as the nucleus accumbens and the amygdaloid complex. In addition, following prolonged periods of abstinence, even after somatic withdrawal signs have vanished, responsiveness of these systems to drugs of abuse remains abnormal. This suggests that these two neurotransmitters may play a substantial role in the long-lasting, enduring changes typical of the addictive process and may represent ideal targets for pharmacological intervention aimed at normalizing forms of neural plasticity impaired after chronic drug intake.