Over the last 15 years, significant improvements in patient outcome have occurred such that heart transplantation is now considered an established therapy with a high likelihood for short-term success. However, the emotional, financial, social and medical burdens placed on patients and families remain enormous and heart transplantation therapy remains palliative. Indeed, most children transplanted in infancy and childhood are not predicted to survive to adulthood. The immunosuppressive regimens have many inherent risks including infections, malignancy and multiple end-organ toxicities. Furthermore, these agents have had little impact on the development of chronic rejection, the leading cause of death late after transplantation. The central paradigm driving this integrated SCCOR proposal is that further improvements in clinical outcome following pediatric heart transplantation depend upon novel strategies that link basic science advances with evidence-driven modifications in clinical protocols. This SCCOR proposal will bring together experts in the fields of pediatric cardiology (cardiac transplantation) and cardiac surgery, immunology, infectious disease, molecular genetics, and biostatistics to advance the common goal of developing novel approaches to the management of pediatric heart transplant recipients. Our long-term goals are to: 1. Develop strategies that result in long-term graft acceptance without requiring immunosuppression. 2. Develop strategies to reduce the morbidities related to non-specific immunosuppressive protocols. 3. Identify genetic markers that predict disparities in transplant outcomes in children after transplantation, including racial disparities. 4. Develop non-invasive diagnostic strategies for rejection surveillance that reduce cost and improve quality and length of life. This Pediatric CV SCCOR proposal addresses each of these areas with novel, hypothesis driven projects to rapidly and significantly advance the state-of-the-art care for pediatric heart transplant recipients.