This Funding Opportunity Announcement (FOA) issued by the National Institute of Neurological Disorders and Stroke (NIINDS), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute on Aging (NIA), and National Institute on Deafness and Other Communication Disorders (NIDCD), National Institutes of Health (NIH), solicits Research Project Grant (R01) applications from institutions/ organizations that propose to find brain mechanisms to improve and develop new approaches to functional recovery after stroke. While stroke is the third leading cause of death in the United States, it is the leading cause of long-term disability in the American population. The Stroke Progress Review Group in 2006 identified the problem of brain repair and rehabilitation after stroke as a major priority for stroke research. In the last decade the major research efforts were directed toward treatment of the acute stroke: reestablishing perfusion of the affected areas, and minimizing the neuronal damage. With the advance of acute stroke treatment, the issues of functional restoration and post-stroke rehabilitation have become increasingly important. At the same time, our understanding of brain responses to stroke-induced damage, brain repair and functional recovery remains relatively poor. Post-stroke rehabilitation is a significant component of stroke treatment in the clinic. Nonetheless, most rehabilitation practices are empirical, rely on behavioral approaches, and are not based on data from large-scale randomized, controlled clinical trials. Relatively little research has been done on the mechanisms of brain repair and plasticity and their relation to behavioral and functional recovery, which are crucial for patients with lifetime consequences of this catastrophic event. This FOA seeks to expand studies on basic brain mechanisms of repair and plasticity after stroke, and on factors that influence these mechanisms. In addition, methods and approaches to improve and enhance reparative processes may be investigated, toward the goal of optimizing and developing promising new approaches to rehabilitation and functional recovery after stroke.