Of the 60,000 patients receiving heart transplants between 1982 and 2001, approximately 12,000 are currently alive. The high incidence of hyperlipidemia and coronary disease (also known as accelerated graft atherosclerosis, or AGA) in these patients warrants early prophylaxis soon after transplantation with 3-hydroxy-3-methylglutaryl (HMG) Co-A reductase inhibitors (statins). Immunosuppressive agents such as prednisone, cyclosporine, mycophenylate mofetil, and sirolimus are associated with hyperlipidemia. Statins, in addition to lowering cholesterol levels, also benefit cardiac transplant recipients via effects on the immune system and endothelial function. Recent data have demonstrated that statins decrease AGA and mortality rates. Furthermore, greater benefits are seen when statins are started early. The 2 statins shown to decrease mortality in patients after cardiac transplantation are pravastatin and simvastatin, which differ in their metabolism (pravastatin is the only statin with non-cytochrome metabolism) and lipophilicity (pravastatin is less lipophilic). Although the benefit of simvastatin has been shown to extend to 8 years after transplantation, increased adverse effects in other studies with higher doses of simvastatin have resulted in new prescribing recommendations, which state that the dose of simvastatin should probably not exceed 10 mg with cyclosporine or gemfibrozil and 20 mg with amiodarone or verapamil. The evidence for potential benefits, interactions, and adverse effects of other potential lipid-lowering drugs for this patient population, such as fibrates, niacin, fish oil, cholestyramine, and ezetimibe, are also discussed. A summary algorithm is proposed, including approaches to patients with statin-associated musculoskeletal symptoms and patients with inadequate results after initial statin therapy.