Although stroke is the third leading cause of death in the United States, it is the significant disability among survivors that has the greatest impact on healthcare and society. It is currently accepted that comprehensive rehabilitation programs improve outcome following stroke. We are now trying to discern which specific therapeutic approaches work and which do not. Years of animal research have resulted in a better understanding of what occurs in the brain following stroke and how the brain may reorganize in response to treatment. Repetitive use of the involved extremities appears key to optimal behavioral recovery and optimal brain reorganization. The advent of technology such as functional magnetic resonance imaging and transcortical magnetic stimulation has allowed the study of brain reorganization following stroke and rehabilitation in humans. Certain drugs also appear to influence neuroplasticity after stroke. Timing of therapy and drug delivery appears crucial; the optimal "critical period" has not yet been clearly identified. New approaches are slow to reach widespread adoption. Neural transplantation combined with repetitive training approaches produces behavioral recovery in animals and offers hope for the future.