According to the dopamine (DA) hypothesis of reward, DA systems in the brain, particularly in the nucleus accumbens, are thought to directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food, water and sex, as well as various drugs of abuse. However, there are numerous problems associated with this hypothesis. Interference with accumbens DA transmission does not substantially blunt primary motivation for natural rewards such as food, but it does disrupt the propensity of animals to engage in effortful responding to obtain food. Electrophysiological and voltammetric studies indicate that novel stimuli, conditioned stimuli that predict reward, and instrumental behaviors that deliver natural rewards all act to stimulate DA activity. Accumbens DA acts as a modulator of several functions related to motivated behavior, and can influence normal and pathological cognitive function, activational aspects of motivation, anergia or psychomotor slowing in depression, the impact of conditioned stimuli, plasticity and a variety of sensorimotor functions.