One approach to pursuing questions about the neural substrates that support substance abuse-related behaviors involves the use of animal models. Carefully controlled animal experiments can be conducted without the confounds commonly found in studies of human addicts, such as polydrug abuse, variable drug history and premorbid psychiatric conditions. The present paper considers the orbitofrontal and related limbic prefrontal cortex in the context of such models of substance abuse. First, the importance of recognizing the heterogeneous structural and functional nature of orbitofrontal cortex in both rodents and primates is addressed, and the results of studies involving the prefrontal cortex in substance abuse-related behaviors are considered in light of this diversity. Second, data from metabolic mapping studies are described that indicate that the pattern of functional activity within medial and orbitofrontal cortex shifts as the duration of exposure to drugs such as cocaine is extended. These functional differences, in turn, may reflect progressive phases of the addictive process. In order to understand the neurobiological consequences of long-term drug use, it will be important to establish the differing roles played by distinct anatomical territories within orbital and medial prefrontal cortex during the course of chronic substance abuse.