The development of colorectal cancer in ulcerative colitis is a function of disease duration, with the risk approaching 14% at 25 years. Colitic cancer has become an issue in the last decades, as the availability of effective immune suppressors has reduced resort to curative colectomies. Scrutiny of the available drug options for ulcerative colitis has generated solid evidence of a chemopreventive role of mesalamines. Recent studies on the thiopurines azathioprine and mercaptopurine have unraveled the ability of these drugs to reduce inflammation and influence adaptive immunity by enhancing apoptosis. This evidence, speaking in favor of a chemopreventive role of thiopurines, has not been supported until recently by clinical studies. By contrast, endoscopic and clinical data in our hands have continued to suggest such a role: of a cohort of ulcerative colitis patients treated with azathioprine for 17 years, those on active treatment had no mucosal inflammation on endoscopy and overall none in this cohort developed cancer. This retrospective data have now been validated by cutting-edge information from a prospective nationwide study from an independent group which found a significant chemopreventive effect of azathioprine in those with extended longstanding colitis. Combination of our single-center experience with the data from this large study strongly indicates that the immune modulatory properties of thiopurines can translate into clinically meaningful anti-cancer activity in colitis. These results are likely to influence the medical choices of inflammatory bowel disease caregivers in the decades to come.