The pathology of inflammatory bowel diseases is driven by the inflammatory signaling pathways associated with mucosal epithelial damage. Myeloid cells are known to play an essential role in medating epithelial inflammatory responses during injury. However, the precise role of these cells in stimulating intestinal inflammation and the subsequent tissue damage is unclear. Here, we show that expression of integrin-linked kinase (ILK) in myeloid cells is critical for epithelial inflammatory signaling during colitis induced by dextran sodium sulfate (DSS). Myeloid-ILK deficiency significantly ameliorates the pathology of experimental colitis. In response to DSS, colonic infiltration of neutrophils and inflammatory cytokine production are impaired in myeloid-ILK-deficient mice and the activation of epithelial nuclear factor kB and phosphatidylinositol 3-kinase signaling pathways are restrcited by myeloid-ILK deficiency. In contrast, reduced epithelial damage in myeloid-ILK-deficient mice is correlated with elevated levels of epithelial Stat3 activation and cellular proliferation. We have also shown that myeloid-ILK-dependent inflammatory signaling in the mucosal epithelium can be therapeutically targeted by the pharmacological inhbition of ILK during experimental colitis. Collectively, these findings identify myeloid-ILK as a critical regulator of epithelial inflammatory signaling pathways during colitis and as a consequence targeting myeloid-ILK could provide therapeutic benefit. Since patients with inflammatory bowel diseases are at increased risk for colon cancer and aberrantly elevated ILK activity is also associated with a wide variety of human cancers, we have investigated the effect of myeloid-ILK in mouse models of colitis-associated and APCmin-driven colon carcinogenesis. Our observations show that myeloid cell specific ILK deficient mice have a significant reduction in tumour burden compared with the control mice. Overall, our findings implicate ILK as a potential target for therapeutic intervention in both inflammatory diseases and cancers.