Numerous investigations indicate that the nucleus accumbens (Acb) is an important neural substrate mediating the reinforcing properties of 'natural' rewards (food or water) as well as abused substances. Here, our electrophysiological studies that examined Acb cell firing within seconds of lever press responding for intravenous cocaine vs. water or food reinforcement in rats are reviewed. Initial investigations revealed that a subset of Acb neurons exhibits four types of firing patterns within seconds of the reinforced response for intravenous cocaine during self-administration sessions. Three of those four cell types were also observed during water reinforcement sessions. In a subsequent study, the activity of the same Acb neurons was examined in rats responding on multiple schedules for either two distinct 'natural' reinforcers (water and food), or one of those 'natural' reinforcers and the intravenous self-administration of cocaine. The results showed that the majority of neurons tested exhibited similar, overlapping neuronal firing patterns across the two 'natural' reinforcer conditions. In contrast, the majority of neurons examined displayed differential, nonoverlapping firing patterns relative to operant responding for water (or food) vs. cocaine reinforcement. Additional studies that examined the role of associative factors on Acb cell firing during cocaine self-administration sessions are reviewed. Collectively, these findings illustrate the dynamic nature of Acb cell firing in behaving animals, and provide insight into how Acb neurons process information about goal-directed behaviors for 'natural' reinforcers vs. abused substances.