Inflammation and cancer are linked, particularly for tumors of the gastrointestinal tract. TIR8 (or SIGIRR) is a member of the IL-1/Toll-like receptor family with inhibitory activity on inflammatory reactions and high expression in intestinal mucosa. In this study, Garlanda and colleagues report that Tir8-deficient mice exhibited dramatic intestinal inflammation in response to dextran sulfate sodium salt (DSS) administration and showed increased susceptibility to carcinogenesis in response to azoxymethane and DSS, associated to increased permeability and local production of prostaglandin E₂, proinflammatory cytokines, and chemokines. The cover image shows numerous high-grade adenomas and a single low-grade adenoma almost completely obliterating the rectal lumen in a Tir8-deficient mouse. These results are consistent with the hypothesis that TIR8, by negatively regulating intestinal inflammation, plays a nonredundant role in the control of the protumor activity of chronic inflammation in the gut. Further studies on polymorphisms at the TIR8 locus in human colon cancer and its value as a target for therapeutic intervention are warranted. For details, see the article by Garlanda and colleagues on page 6017 of this issue.