Liver transplantation is the treatment of choice for early-stage hepatocellular carcinoma (HCC) in the setting of cirrhosis and portal hypertension. Calcineurin inhibitors (CNIs) form the backbone of immunosuppressive therapy in liver transplant recipients. However, CNIs have inhibitory effect on T cell activity and suppress cancer immunosurveillance. Mammalian target of rapamycin inhibitors (mTORis) suppress cell proliferation, have anti-angiogenetic effect, and have been shown to reduce tumor growth in preclinical models. Several retrospective studies have suggested that mTORi-based immunosuppression as compared to CNIs decreases the risk of recurrence of HCC after liver transplantation. However, a large international multicenter randomized control trial showed no significant benefit of mTORis over CNIs for long-term overall survival or recurrence-free survival. Given that mTORis have the added advantage of stabilizing and/or improving renal function, utilizing mTORis to minimize the exposure to CNI may be considered in patients who have received liver transplantation for HCC.