Orthotopic heart transplantation (OHT), first accomplished in 1967, is currently performed in over 2000 patients per year at hundreds of centers worldwide. Selection criteria include end-stage heart failure with a limited life expectancy, intractable angina due to inoperable coronary artery disease, malignant ventricular arrhythmias refractory to maximal therapy, and unresectable cardiac tumors. While early immunosuppression was based on azathioprine and steroids, the current success of OHT is based on the addition of cyclosporine A (CyA) to this regimen. At Columbia-Presbyterian Medical Center, steroids and azathioprine are given perioperatively, and cyclosporine (OKT3 in patients with renal dysfunction) begun postoperatively. Survival rates at our institution parallel those reported by other centers, with 1- and 5-year actuarial survival of 85% and 70%, respectively. The most frequent causes of early mortality are allograft rejection and infection, while graft coronary artery disease (CAD) is responsible for most deaths occurring after the first post-transplant year. Regular endomyocardial biopsy is used to monitor for rejection, which occurs in 55% of patients within the first year. Mild or asymptomatic rejection is managed with oral steroids, followed by intravenous steroids and/or OKT3 or anti-thymocyte globulin (ATG) in refractory cases. Graft CAD occurs in 45% of patients surviving 3 years, and may require retransplantation. Heart transplantation is a proven, effective form of cardiac replacement. The recent trend of increasingly critically ill transplant candidates, however, has driven the costs of OHT to unprecedented levels. This issue, as well as the continuing organ short-age and current developments in mechanical cardiac assistance and xenotransplantation will undoubtedly assure a continually evolving role for cardiac transplantation in the treatment of endstage heart disease.