Leflunomide is a synthetic isoxazole-derivative drug that possesses both immunosuppressive and antiviral properties. Although its only US FDA-approved indication is for the treatment of rheumatoid arthritis, accumulating clinical experience in addition to animal study data makes it an appealing option for patients who are in need of reduction of immunosuppression in the setting of resistant cytomegalovirus infection or BK virus nephropathy, or in renal transplant recipients with chronic allograft dysfunction. While concern over adverse effects such as hepatotoxicity and hemolytic anemia cannot be ignored and there has yet to be a prospective randomized trial for its use in transplantation, its careful usage under close monitoring may provide the best chance for patients who risk allograft rejection during the time of immunosuppressive reduction as they attempt to eradicate BK virus or cytomegalovirus. At the present time, its use as a first-line agent in lieu of mycophenolate mofetil or sirolimus cannot be recommended.