The prefrontal cortex (PFC) is implicated in a number of higher cognitive functions as well as processing emotions and regulation of stress responses. Hemispheric specialization of the PFC in humans in emotional processing is well documented, and there is evidence that a similar functional lateralization is present in all mammals. Recent findings suggest the possibility of an intrinsic structural hemispheric asymmetry in the rat medial PFC (mPFC). Specifically, interhemispheric differences have been found in the architecture of pyramidal cell apical dendritic trees together with hemispheric asymmetry in cell proliferation including gliogenesis. It is now well established that chronic stress has a profound impact on neural plasticity in a number of corticolimbic structures and affects the etiology, pathophysiology, and therapeutic outcome of most psychiatric disorders. We summarize recent experimental data documenting pronounced dendritic remodeling of pyramidal cells and suppressed gliogenesis in the mPFC of rats subjected to chronic stress or to artificially elevated glucocorticoid levels. The stress affect on these structural elements seems to be hemispheric specific, often abolishing or even reversing natural asymmetries seen at the cellular level. We discuss these preclinical observations with respect to clinical findings that show impaired function, altered lateralization and histopathological changes in the PFC in psychiatric patients. We argue that it is important to define the kinds of structural changes that result from long-term stress exposure because this knowledge will improve the identification of cellular endophenotypes in various psychiatric disorders.