The first randomized controlled trials demonstrating the efficacy of thiopurines in inducing and maintaining remission in ulcerative colitis (UC) [1] and Crohn’s disease [2] were published in the 1980s. At that time, bone marrow toxicity [3,4], liver toxicity [5], immunoallergic reactions [6], and concerns about teratogenicity [7] of 6-mercaptopurine (6-MP) and azathioprine were already known, and the clinical use of thiopurines was restricted to the most severely ill patients in a “step-up” approach. Thiopurines have since been increasingly recommended for various forms of chronic active IBD [8,9], leading to their extensive clinical use from the end of the 1990s, with the proportion of patients exposed to the drugs now reaching 40% for Crohn’s disease and 20% for UC in some Western countries [10]. This has enabled, from a methodological feasibility point of view, the identification of new risks (hepatic nodular regenerative hyperplasia [NRH]) and the quantification of some others (benign and opportunistic infections, lymphomas, and non-melanoma skin cancers) through observational studies from tertiary care cohorts or very large population databases.