6-Mercaptopurine and azathioprine have become important therapeutic options for patients with inflammatory bowel disease (IBD). Although accumulating data in the literature have supported the use of these immunomodulators in the management of IBD, marked variation exists in the pattern of clinical practice regarding azathioprine or 6-mercaptopurine therapy in patients with IBD. This article provides a critical review of the data on the clinical efficacy and toxicities of 6-mercaptopurine and azathioprine in the management of IBD. Emerging literature on the potential application of pharmacogenetic testing and metabolite monitoring are also discussed.