With the increasingly widespread use of immunosuppressive and biologic agents for the treatment of Crohn's disease and ulcerative colitis come concerns about potential long-term consequences of such therapies. Disentangling the potential confounding effects of the underlying disease, its extent, severity, duration, and behavior, and concomitant medical therapy has proven to be exceedingly difficult. Unlike the case in rheumatoid arthritis, the overwhelming preponderance of population-based evidence suggests that a diagnosis of inflammatory bowel disease (IBD) is not associated with an increased relative risk of lymphoma. However, well-designed studies that evaluate the potential modifying effect of IBD severity have yet to be performed. Although the results from hospital- and population-based studies have conflicted, the results of a recent meta-analysis suggest that patients receiving purine analogs for the treatment of IBD have a lymphoma risk approximately 4-fold higher than expected. Analyses of lymphoma risk in patients receiving biologic agents directed against tumor necrosis factor-alpha are confounded by concomitant use of immunosuppressive agents in most of these patients. Nevertheless, there may be a small but real risk of lymphoma associated with these therapies. Although the relative risk of lymphoma may be elevated in association with some of the medical therapies used in the treatment of IBD, this absolute risk is low. Weighing the potential risk of lymphoma associated with select medical therapies against the risk of undertreating IBD will help physicians and patients to make more informed decisions pertaining to the medical management of IBD.