Orthotopic liver transplantation is currently the procedure of choice for patients with end-stage liver disease, with survival rates greater than 90% and 80% at 1 and 5 years, respectively. These excellent results are largely due to knowledge of the natural history of liver diseases, improved surgical techniques and postoperative management of recipients, and availability of active antibacterial, antiviral, and antifungal drugs, as well as the development and application of potent immunosuppressive drugs. The introduction of calcineurin inhibitors (CNI)-cyclosporine and tacrolimus-has been one of the most important advances in solid-organ transplantation. Nevertheless, the survivals have been impaired by an increasing prevalence and long-term consequences of drug-related cardiovascular diseases, de novo neoplasias, recurrence of both viral and tumor diseases, and posttransplant renal dysfunction. Strategies for immunosuppression include the design of individualized protocols with the objective to increase immunologic efficacy with a reduced number and severity of secondary effects, according to the clinical status and the posttransplant complications: renal failure, de novo neoplasia, recurrent hepatocellular carcinoma. In this setting, new immnunosuppressive protocols have been investigated to include reduction in or withdrawal of CNI.