Although adrenal steroid receptors are distributed widely throughout the central nervous system, specific limbic and cortical regions targeted by stress hormones play a key role in integrating behavioral and physiological responses during stress and adaptation to subsequent stressors. When the stressor is of a sufficient magnitude or prolonged, it may result in abnormal changes in brain plasticity that, paradoxically, may impair the ability of the brain to appropriately regulate and respond to subsequent stressors. Here we review how repeated stress produces alterations in brain plasticity in animal models, and discuss its relevance to behavioral changes associated with these regions. Interestingly, prolonged stress produces opposing effects on structural plasticity, notably dendritic atrophy and excitatory synapse loss in the hippocampus and prefrontal cortex, and growth of dendrites and spines in the amygdala. The granule cells of the dentate gyrus are also significantly affected through a decrease in the rate neurogenesis following prolonged stress. How functional impairments in these brain regions play a role in stress-related mental illnesses is discussed in this context. Finally, we discuss the cumulative impact of stress-induced structural plasticity in aging.