The purine analogues 6-mercaptopurine (6-MP) and azathioprine have been found to be safe and efficacious in both inducing remission of Crohn's disease in adults and maintaining remission in adults and children. In addition, steroid-sparing effects are demonstrable in trials of both adults and children with Crohn's disease. Anecdotal reports of adults and very limited data from children also suggest that azathioprine and 6-MP might help prevent postoperative recurrence of Crohn's disease. Regarding safety, adults and children reported similar rates of adverse effects from the use of these agents: reported adverse effects in adults included significant infection (7.4%), pancreatitis (3.3%), neoplasm (3.1%), bone marrow suppression (2.0%), allergy (2.0%), and drug-induced hepatitis (0.3%). Most studies also suggest there is little, if any, probability that immunomodulatory therapy might increase the risk of malignancy in patients with Crohn's disease. Data are too limited to guide clinical decisions on how long immunomodulatory therapy should be continued, whether it is safe to take azathioprine and 6-MP during pregnancy, and whether men can take these agents at the time of conception. Although 6-MP and azathioprine have been used safely for over 30 years, the recent commercial availability of thiopurine methyltransferase (TPMT) genotype/phenotype testing and 6-MP metabolite testing offers the promise of limiting potential toxicity even more. As a result, these agents will continue to play a central therapeutic role for all clinicians caring for children or adults with Crohn's disease.