Neurobiological models of substance dependence hypothesize that addiction results from interplay between positive and negative reinforcement. Positive reinforcing effects of drugs are mediated through dopamine transmission in the striatum, while negative reinforcement involves the central stress systems. Substance dependence leads to persistent changes in the brain motivational systems. Neuropsychological research showed impairment in decision-making that could be related to a dysfunction in the ventromedial prefrontal cortex. A further critical region is the insula that could be involved in the impaired insight in addictive behaviour and in the mediation of the conscious urge to take the drug. Neurobiological and neuropsychological perspectives are integrated here in a model combining impulsive subcortical and dopamine-related processes with dysfunction of cortical inhibition and cognitive deficits.