Advances in surgical techniques, immunosuppressive medications, and robust infectious disease prophylaxis have resulted in liver transplantation becoming the treatment of choice for patients with end-stage liver disease and unresectable hepatocellular carcinoma. Nonetheless, organ transplantation is not without risk. Unexpected donor-derived disease transmission is a newly recognized risk that complicates approximately 0.2% of all organ transplants. We review the epidemiology of donor-derived infectious diseases and methods of risk mitigation with a focus on liver transplantation. Liver Transpl 19:575–585, 2013. © 2013 AASLD.