Molecular oxygen (O2) is a vital element in human survival and plays a major role in a diverse range of biological and physiological processes. Although normobaric hyperoxia can increase arterial oxygen content ([Formula: see text]), it also causes vasoconstriction and hence reduces O2 delivery in various vascular beds, including the heart, skeletal muscle, and brain. Thus, a seemingly paradoxical situation exists in which the administration of oxygen may place tissues at increased risk of hypoxic stress. Nevertheless, with various degrees of effectiveness, and not without consequences, supplemental oxygen is used clinically in an attempt to correct tissue hypoxia (e.g., brain ischemia, traumatic brain injury, carbon monoxide poisoning, etc.) and chronic hypoxemia (e.g., severe COPD, etc.) and to help with wound healing, necrosis, or reperfusion injuries (e.g., compromised grafts). Hyperoxia has also been used liberally by athletes in a belief that it offers performance-enhancing benefits; such benefits also extend to hypoxemic patients both at rest and during rehabilitation. This review aims to provide a comprehensive overview of the effects of hyperoxia in humans from the "bench to bedside." The first section will focus on the basic physiological principles of partial pressure of arterial O2, [Formula: see text], and barometric pressure and how these changes lead to variation in regional O2 delivery. This review provides an overview of the evidence for and against the use of hyperoxia as an aid to enhance physical performance. The final section addresses pathophysiological concepts, clinical studies, and implications for therapy. The potential of O2 toxicity and future research directions are also considered.