Leflunomide, an inhibitor of dihydroorotase dehydrogenase and thereby pyrimidine synthesis, was approved for treatment of rheumatoid arthritis in 1998. During the following years, leflunomide was used in various preclinical studies as a potential cancer treatment; at the same time, more mechanisms underlying the anticancer effect of leflunomide were identified. Thus, leflunomide has been identified as a potent anticancer drug. This article summarizes the mechanisms as well as results of leflunomide in the evolving field of cancer therapy. (C) 2018 Elsevier Inc. All rights reserved.