The effects of extreme disuse or overuse of the limbs in rat models of Parkinson's disease and stroke are discussed. In unilaterally lesioned rats, immobilizing one forelimb in a cast forces complete disuse of this limb and extreme overuse of the uncasted limb. This procedure has diverse effects on histological and behavioral outcomes in these models, depending upon how and when it is applied relative to the lesion. Effects on behavioral outcome, post-lesion plasticity events, and expression of trophic factors are discussed. The effects of forced disuse or overuse vary among lesion types and can include neuroprotection, changes in synaptogenesis, or even exaggeration of tissue loss. The diversity of behavior-driven structural changes in the brain underscores the potential importance of carefully tailoring physical restorative therapy to specific neurological problems in order to optimize outcomes. In addition, we stress the need to recognize the reciprocal influence that behavior and the brain can have upon each other.