The question of whether BD is primarily a developmental disorder or a progressive, neurodegenerative disorder remains unresolved. Here, we review the morphometric postmortem and neuroimaging literature relevant to the neuropathology of bipolar disorder (BD). We focus on the medial prefrontal cortex (mPFC) network, a key system in the regulation of emotional, behavioral, endocrine, and innate immunological responses to stress. We draw four main conclusions: the mPFC is characterized by (1) a decrease in volume, (2) reductions in neuronal size, and/or changes in neuronal density, (3) reductions in glial cell density, and (4) changes in gene expression. These data suggest the presence of dendritic atrophy of neurons and the loss of oligodendroglial cells in BD, although some data additionally suggest a reduction in the cell counts of specific subpopulations of GABAergic interneurons. Based on the weight of the postmortem and neuroimaging literature discussed herein, we favor a complex hypothesis that BD primarily constitutes a developmental disorder, but that additional, progressive, histopathological processes also are associated with recurrent or chronic illness. Conceivably BD may be best conceptualized as a progressive neurodevelopmental disorder.