Numerous investigations have implicated the nucleus accumbens (NA) as an important neural substrate involved in mediating reinforcement-related processing. Electrophysiological studies in behaving animals enable a direct examination of cellular mechanisms underlying this process via characterization of NA activity at critical times during responding for food, water, or drug reward. Electrophysiological studies are reported that examined the activity of NA neurons during water- and cocaine-reinforced responding in rats. These studies reveal that some NA neurons exhibit changes (increases or decreases) in firing rate synchronized to the response-contingent delivery of water or cocaine. Furthermore, the sampled population of NA neurons exhibited less synchronized cell firing during the response for cocaine than for the water reward. NA activity during cocaine self-administration was explicitly coupled to the behavioral state of the animal and was markedly influenced by the stimulus context in which the drug was delivered. These findings are discussed with respect to the dynamic properties of NA activity and its importance as an underlying cellular substrate mediating reinforcement-related events in the behaving animal.