Stimulator of IFN genes (STING) is a cytoplasmic innate immune sensor for cyclic dinucleotides that also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. Although STING has important functions in the host defense against pathogens and autoimmune diseases, its physiological role in cancer is unknown. In this study, we show that STING-deficient mice are highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibit significant intestinal damage and overt proliferation during early stages of tumorigenesis. Moreover, STING-deficient mice fail to restrict activation of the NF-κB–and STAT3-signaling pathways, which leads to increased levels of the proinflammatory cytokines IL-6 and KC. Therefore, our results identified an unexpected and important role for STING in mediating protection against colorectal tumorigenesis.