Although it is now accepted that chronic inflammation plays an essential role in tumorigenesis, the underlying molecular mechanisms linking inflammation and cancer remain to be fully explored. Inflammatory mediators present in the tumor microenvironment, including cytokines and growth factors, as well as reactive oxygen species (ROS) and reactive nitrogen species (RNS), have been implicated in the etiology of inflammation-associated cancers. Epithelial NADPH oxidase (Nox) family proteins, which generate ROS regulated by cytokines, are upregulated during chronic inflammation and cancer. ROS serve as effector molecules participating in host defense or as chemo-attractants recruiting leukocytes to wounds, thereby influencing the inflammatory reaction in damaged tissues. ROS can alter chromosomal DNA, leading to genomic instability, and may serve as signaling molecules that affect tumor cell proliferation, survival, metabolism, angiogenesis, and metastasis. Targeting Noxs and their downstream signaling components may be a promising approach to pre-empting inflammation-related malignancies.