Hypoxia-inducible factors (HIFs) mediate adaptation to low O2, or hypoxia, are important at every stage of tumor initiation, and impact the progression of a variety of diseases, including colorectal cancer. This body of work investigates the role of hypoxia and HIF-mediated signaling in both tumor cells and macrophages across the natural history of inflammation-induced cancers. First, the effect of HIF inhibition in tumor parenchyma and stroma in extant colitis-associated colon carcinomas (CAC) is investigated using acriflavine (ACF), a naturally occurring compound known to repress HIF transcriptional activity. Pharmacologic HIF inhibition represents a novel therapeutic strategy for cancer treatment and data indicates ACF treatment halts the progression of an autochthonous model of established CAC in immunocompetent mice and does so largely through HIF-dependent means. These results suggest pharmacologic HIF inhibition in multiple cell types, including epithelial and innate immune cells, significantly limits tumor growth and progression. Second, myeloid specific deletion (LysMCre) of the HIF constitutive binding partner ARNT is studied in the setting of acute and chronic inflammatory responses that eventually result in inflammation-associated cancer development. Data indicates loss of ARNT results in severe macrophage defects including decreased edema and inflammatory infiltrate in an acute model of skin inflammation and lower stage disease and decreased tumor inflammation in a model of CAC. Collectively, these data suggest the hypoxic response is necessary for sustained inflammation and tumor progression and may provide a link between chronic inflammatory conditions and cancer development.