Oxygen administration is often assumed to be required for all patients who are acutely or critically ill. However, in many situations, this assumption is not based on evidence. Injured body tissues and cells throughout the body respond both beneficially and adversely to delivery of supplemental oxygen. Available evidence indicates that oxygen administration is not warranted for patients who are not hypoxemic, and hyperoxia may contribute to increased tissue damage and mortality. Nurses must be aware of implications related to oxygen administration for all types of acutely and critically ill patients. These implications include having knowledge of oxygenation processes and pathophysiology; assessing global, tissue, and organ oxygenation status; avoiding either hypoxia or hyperoxia; and creating partnerships with respiratory therapists. Nurses can contribute to patients’ oxygen status well-being by being proficient in determining each patient’s specific oxygen needs and appropriate oxygen administration.