PURPOSE OF REVIEW: The purpose is to establish a theoretical framework by which new interventions for poststroke rehabilitation may be developed incorporating knowledge of neuroplasticity and the critical ingredients of rehabilitation. RECENT FINDINGS: Large phase III randomized controlled trials (RCTs) are rare in neurorehabilitation, and the results of those that have been completed are perplexing because the experimental and control treatments were not different when matched for activity level. In addition, the outcome measures used to define treatment effects reflected behavioral endpoints, but did not reveal how neuroplastic mechanisms or other mechanistic factors may have contributed to the treatment response. Knowledge of both the neurophysiologic basis of recovery and key elements of interventions that drive motor learning, such as intensity and task progression, are critical for optimizing future poststroke motor rehabilitation clinical trials. SUMMARY: Future neurorehabilitation RCTs require a better understanding of the interaction of interventions and neurophysiological recovery in order to target interventions at specific neurophysiologic substrates, develop a more clear understanding of the impact of intervention parameters (e.g. dose, intensity), and advance discussions regarding optimal ways to partner medical and rehabilitation interventions in order to improve outcomes.