Leflunomide (LEF) is a prodrug that is rapidly converted to its active metabolite A77 1726, that inhibits the novo pyrimidine nucleotide biosynthesis, mediated especially by the dihydroorotate dehidrogenase (DHODH). DMARD properties were documented in rheumatoid arthritis with efficacy, safety and limiting of radiological progression demonstrated in multiple studies. LEF has been also used in other autoimmune diseases, like Psoriatic Arthritis, Wegener granulomatosis, Systemic Lupus Erythematosus, Sarcoidosis and others. This article reviews the place of LEF in clinical practice and outlines its potential applications beyond the officially recognized indication: rheumatoid arthritis (RA).