Hypoxemia, caused by disrupted vasculature, is a key factor that limits wound healing. Correcting hypoxemia through the administration of supplemental oxygen (O(2)) can have significant beneficial impact on wound healing in the perioperative and outpatient settings. Beyond its role as a nutrient and antibiotic, O(2) may support vital processes such as angiogenesis, cell motility, and extracellular matrix formation. Recent discoveries highlight a novel aspect, addressing the role of O(2) in wound healing via the production of reactive oxygen species (ROS). Almost all wound-related cells possess specialized enzymes that generate ROS (including free radicals and H(2)O(2)) from O(2). Defect in these enzymes is associated with impaired healing. Low wound pO(2) is expected to compromise the function of these enzymes. At low concentrations, ROS serve as cellular messengers to support wound healing. The use of systemic hyperbaric O(2) therapy presents potential advantages, as well as risks. There is evidence to suspect that the use of pressure and systemic pure O(2) may not be essential in wound care. Elimination of these factors by using sub-pure systemic O(2) under normobaric conditions may significantly minimize the risk of O(2) toxicity. Furthermore, opportunities to treat dermal wounds using topical O(2) therapy warrant further investigation. Given that many growth factors require ROS for their function, it is reasonable to assume that approaches to correct wound pO(2) will serve as an effective adjunct in treating chronic wounds.