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Interleukin 33 (IL33) is an unusual cytokine with many purported functions in tumorigenesis. IL33 expression is associated with poor prognosis in multiple solid tumors and is also released during inflammatory colitis. Because many different types of immune cells express the receptor for IL33, its effects on immune functions are broad. It can promote Th2, Th1, and cytotoxic responses. However, IL33 also appears to play a role during homeostatic renewal of the epithelial lining of the gut. Therefore, Eissmann et al. examined the role of IL33 during the initiation of sporadic colorectal cancers, which accounts for the majority of the disease occurrences in humans. Through the use of a sporadic colon cancer model in mice that lacked the receptor for IL33, they determined that IL33 signaling can protect against tumor initiation. The authors found that IL33 signaling in mice increased IFNγ production and decreased the number of Tregs in the colon, which correlates with findings in human patients with colon cancer. Read more starting on page 409 of this issue. Micrograph of infiltrating macrophages in a colon tumor of receptor-ablated mice from Supplementary Fig. S5. Artwork by Lewis Long.