Improvement of motor activity may occur after stroke. It may be because of recovery of marginally functional neurons. It may also occur by relearning, a process that strengthens existing pathways and may lead to new functional or structural changes- neuroplasticity. Clinical investigation into the treatment of chronic pain after thalamic infarction has shown improvement in motor function when pain relief is achieved with motor cortex stimulation. More recently, laboratory studies in rats and primates demonstrate significant improvement in forelimb reaching tasks in rats and primates after induced ischemic cortical infarction when rehabilitation is paired with stimulation of the injured cortex and cortical margin at low frequency (50 Hz). Structural changes have also been observed. Dendritic density in layer V of the cortex near the lesion increases after cortical stimulation, consistent with a restorative cortical plasticity. Also, stimulation combined with rehabilitation increases the area of the injured cortex from which movements can be evoked in response to stimulation of the injured cortex in rats. Unilateral cortical stimulation reduces secondary cortical hyperexcitability in the impaired hemisphere after stroke. These findings form the basis for the first clinical study motor cortex stimulation after chronic stroke in humans. A prospective, randomized multicenter study of subthreshold motor cortical electrical stimulation during rehabilitation in patients has been completed. The eight patients entered into this study had weakness from a stroke that occurred at least four months before enrollment. Results demonstrate that the treatment is safe. In addition, there was significant improvement in upper extremity function. These improvements persisted through the 12-week follow-up assessment period after completion of stimulation and rehabilitation. Recently, non-invasive transcranial magnetic stimulation of the motor cortex demonstrates improvements in hand function that persist after stimulation for at least 25 minutes. Such work represents a paradigm shift in the approach towards rehabilitation of the stroke-injured brain away from pharmacologic flooding of neuronal receptors, instead towards targeted physiologic stimulation.