Purpose of reviewLeflunomide is a disease-modifying agent approved for use in rheumatoid arthritis and used off label for other conditions such as systemic lupus erythematosus. It has several properties that generate significant interest for potential use as an immunosuppressive agent in transplantation. This article reviews some of the properties stimulating this appeal and the initial reports on the use of leflunomide in transplantation, ending with a discussion of similar agents in development.Recent findingsIn cell models, leflunomide is able to limit both cellular and humoral immune responses. In animal allograft and xenograft models, leflunomide has demonstrated the ability to prevent or limit acute rejection and slow or reverse chronic rejection processes, independently or in synergy with other immunosuppressive agents. Leflunomide has demonstrated antiviral properties against pathogens of concern in transplant recipients and may have a quite favorable cardiovascular risk profile. Reported use of leflunomide in human transplantation is limited, but two recent reports, one prospective and one retrospective, describe the successful use of this agent in solid organ transplantation.SummaryLeflunomide has several properties that make it an excellent candidate for use in transplantation, but concerns about the prolonged half-life and potential for hepatotoxicity temper the enthusiasm. As it will likely be several years before similar, shorter acting agents are available, continued study is warranted to discern the appropriate use in human transplantation of this currently available agent.