Significance: NADPH oxidases are important sources for regulated generation of reactive oxygen species (ROS). The main ROS produced are superoxide and hydrogen peroxide, both of which are redox signaling molecules in the context of various cellular functions. Redox imbalance due to excessive or insufficient ROS is a hallmark of pathophysiological aspects, including cancer development and progression. Recent Advances: Epigenetic silencing of NADPH oxidases by hypermethylation of their promoter region or of the genes required for their assembly and activity occurs in diseases, such as lung cancer, and may represent an early stage of neoplastic transformation. Critical Issues: Loss of ROS-mediated signaling by epigenetic silencing may promote tumorigenesis. Conversely, increased oxidative stress caused by oncogene-induced overexpression of NADPH oxidases may also drive epigenetic instability. Thus, the cellular redox balance is likely vital in carcinogenesis. Future Directions: NADPH oxidases may serve as prognostic tumor biomarker, especially when their individual expression is confined to accessible tissues, such as mucosal epithelia or blood. Further validation of NADPH oxidase/dual oxidase enzymes as candidate markers will require well controlled, large-scale clinical data sets. This review is focused on NADPH oxidases as targets of epigenetic changes in cancer and on the emerging role of ROS as inducers of epigenetic changes. Antioxid. Redox Signal. 18, 1937–1945.