ABSTRACT: At least twenty-two architectonic areas can be distinguished within the orbital and medial prefrontal cortex (OMPFC). Although each of these areas has a distinct structure and connections, they can be grouped into two “networks,” defined by cortico-cortical connections that primarily interconnect areas within each network. The networks also have different connections to the striatum, medial thalamus, and other brain regions. The orbital network consists of most of the areas in the orbital cortex. It receives several sensory inputs (olfactory, gustatory, visceral afferent, somatic sensory, and visual) that appear to be related to feeding. It also receives many limbic inputs from the amygdala, entorhinal and perirhinal cortex, and subiculum, including a specific projection from the ventrolateral part of the basal amygdaloid nucleus. The orbital network may therefore serve as a substrate to integrate viscerosensory information with affective signals. The medial network consists of areas on the medial frontal surface together with a few select areas in the orbital cortex. These areas have few direct sensory inputs, and their limbic inputs are somewhat different than those to the orbital network (e.g., from the ventromedial part of the basal amygdaloid nucleus). However, they provide the major output from the OMPFC to the hypothalamus and brain stem (especially the periaqueductal gray). The medial network may therefore serve as a visceromotor system to provide frontal cortical influence over autonomic and endocrine function. Connections between the networks presumably allow information flow from viscerosensory to visceromotor systems. In addition to a probable role in eating behavior, this system appears to be involved in guiding behavior and regulation of mood. Lesions of the ventromedial prefrontal cortex result in sociopathic behavior and difficulty in making appropriate choices, whereas functional imaging studies indicate that subjects with unipolar and bipolar depression have abnormal activity in medial and orbital prefrontal areas. Many of these areas also show volume changes and decreased glial number and density in mood-disordered subjects.