The development of cyclosporine was pivotal in allowing cardiac transplantation to become an accepted treatment for patients with end-stage heart disease. More recently, tacrolimus has become available as a useful alternative to cyclosporine, and has been successfully combined with either azathioprine or the newer anti-proliferative agents, mycophenolate mofetil or sirolimus. Numerous randomized clinical trials have demonstrated that tacrolimus is comparable to cyclosporine in terms of overall patient survival and at least equally effective in preventing acute rejection. In addition, tacrolimus has been particularly effective as a rescue treatment in cases where recurrent rejection has occurred with cyclosporine. The adverse effects of tacrolimus differ from those of cyclosporine, and the drug particularly shows an improved profile with respect to hypertension, dyslipidemia, and long-term renal function. These data have recently led to the regulatory approval of tacrolimus for primary immunosuppression in patients undergoing cardiac transplantation in the US.