Tissue injury and inflammation are associated with increased production of reactive oxygen species (ROS), which have the ability to induce oxidative injury to various biomolecules resulting in protein dysfunction, genetic instability, or cell death. However, recent observations indicate that formation of hydrogen peroxide (H2O2) during tissue injury is also an essential feature of the ensuing wound healing response, and functions as an early damage signal to control several critical aspects of the wound healing process. Because innate oxidative wound responses must be tightly coordinated to avoid chronic inflammation or tissue injury, a more complete understanding is needed regarding the origins and dynamics of ROS production, and their critical biological targets. This prospect highlights the current experimental evidence implicating H2O2 in early epithelial wound responses, and summarizes technical advances and approaches that may help distinguish its beneficial actions from its more deleterious actions in conditions of chronic tissue injury or inflammation. J. Cell. Biochem. 115: 427–435, 2014. © 2013 Wiley Periodicals, Inc.