The thiopurines azathioprine and 6-mercaptopurine have been used in the treatment of Crohn's disease and ulcerative colitis for over 40 years. Randomized controlled trials have supported their use in the treatment of active disease, as well as for the maintenance of disease remission. Presently, the most debated issues surrounding the thiopurines include: the role of thiopurine methyltransferase and metabolite-adjusted dosing in enhancing efficacy and minimizing toxicity; the timing of thiopurine use, that is, earlier versus later use during the course of the disease; the selection of thiopurine monotherapy versus combination therapy with an anti-TNF-α; agent; and the safety profile of thiopurines. Accumulated evidence has supported the safety of 6-mercaptopurine/azathioprine use in pregnancy and lactation. Thiopurine therapy in inflammatory bowel diseases is associated with an increased risk of lymphoproliferative disorders. Factoring their proven efficacy over a broad range of clinical scenarios within Crohn's disease and ulcerative colitis together with their overall safety profile and convenient and inexpensive once-daily oral administration, azathioprine and 6-mercaptopurine remain among the mainstays of Crohn's disease and ulcerative colitis therapy.