Innate immune responses are key to maintain adequate host-microbial interactions. However, those signals are needed to efficiently trigger rapid and targeted antimicrobial responses in case of pathogen encounter. Several molecules have evolved to regulate intensity and coordinate signaling to avoid detrimental consequences to the host. Regulation can occur at the cell surface, within the cytoplasm, and at the transcriptional level. Innate immune regulation seems to be equally important than stimulation, as disruption of immunoregulatory molecules modulates the risk for several diseases. This is the case for colitis and inflammatory bowel disease but also colorectal cancer and intestinal infections. In this review, we recapitulate the molecular mechanisms underlying regulation of innate immune signals and mention their implications in several disease states including inflammatory bowel disease.