The prefrontal cortex (PFC) has long been known to be involved in the mediation of complex behavioral responses. Considerable research efforts are directed towards refining the knowledge about the function of this brain area and the role it plays in cognitive performance and behavioral output. In the first part, this review provides, from a pharmacological perspective, an overview of anatomical, electrophysiological and neurochemical aspects of the function of the PFC, with an emphasis on the mesocortical dopamine system. Anatomy of the mesocortical system, basic physiological and pharmacological properties of neurotransmission within the PFC, and interactions between dopamine and glutamate as well as other transmitters within the mesocorticolimbic circuit are included. The coverage of these data is largely restricted to what is relevant for the second part of the review which focuses on behavioral studies that have examined the role of the PFC in a variety of phenomena, behaviors and paradigms. These include reward and addiction, locomotor activity and sensitization, learning, cognition, and schizophrenia. Although the focus of this review is on the mesocortical dopamine system, given the intricate interactions of dopamine with other transmitter systems within the PFC and the importance of the PFC as a source of glutamate in subcortical areas, these aspects are also covered in some detail where appropriate. Naturally, a topic as complex as this cannot be covered comprehensively in its entirety. Therefore this review is largely limited to data derived from studies using rats, and it is also specifically restricted to data concerning the medial PFC (mPFC). Since in several fields of research the findings concerning the function or role of the mPFC are relatively inconsistent, the question is addressed whether these inconsistencies might, at least in part, be related to the anatomical and functional heterogeneity of this brain area.