Many common cancers develop as a consequence of years of chronic inflammation. Increasing evidence indicates that the inflammation may result from persistent mucosal or epithelial cell colonization by microorganisms; including hepatitis B virus and hepatitis C virus, which can cause hepatocellular cancer; human papilloma virus subtypes, which cause cervical cancer, and the bacterium Helicobacter pylori, which can cause gastric cancer. At present, the cause of other chronic inflammatory conditions associated with increased cancer risk, such as ulcerative colitis, is obscure. Particular microbial characteristics as well as the type of the inflammatory response contribute to clinical outcomes via influence on epithelial cell and immune responses. Persistent inflammation leads to increased cellular turnover, especially in the epithelium, and provides selection pressure that result in the emergence of cells that are at high risk for malignant transformation. Cytokines, chemokines, free radicals, and growth factors modulate microbial populations that colonize the host. Thus, therapeutic opportunities exist to target the causative microbe, the consequent inflammatory mediator, or epithelial cell responses. Such measures could be of value to reduce cancer risk in inflammation-associated malignancies.