The ongoing quest of achieving clinical transplantation tolerance has been fueled, in large part, by the success of solid organ transplantation. Long term morbidity following transplantation now is primarily related to complications of immunosuppression (IS) such as malignancy, drug toxicity, or infection. This report provides long term follow-up on a large cohort of operationally tolerant patients, provides clinical guidelines to be considered in IS withdrawal, and identifies future prospects for achieving consistent clinical tolerance following liver transplantation (LT).