Sirolimus (SRL) is a macrolide antibiotic that has potent antifungal and immunosuppressive properties; preclinical studies suggest that SRL may possess a significant antiproliferative influence in vitro. Recently, several studies have documented a negative effect by SRL on both primary tumor growth and the proliferation of metastatic foci in various rodent models of hepatocellular carcinoma (HCC). Orthotopic liver transplantation (OLT) is increasingly becoming a viable treatment option for patients with end stage liver disease and concomitant HCC. As such, an immunosuppressive agent with antineoplastic activity is inherently attractive in the setting of OLT for malignancy. Regrettably, the cumulative experience with SRL-based immunosuppression in this patient population is limited. Herein, the authors review the experience to date with SRL as a primary immunosuppressive agent following OLT, and discuss the clinical implications of SRL-based therapy in OLT recipients with cirrhosis and cancer.