The definitions of hypoxemia and hypoxia, and basic pulmonary anatomy and oxygen delivery are reviewed. Low ambient oxygen, hypoventilation, ventilation-perfusion mismatch, and right-to-left shunt, the four basic mechanisms of hypoxemia are described in detail with patient examples. For the sake of completion, a fifth mechanism of hypoxemia that is rarely seen in human disease is described. Because getting oxygen into the blood stream is only half the story, mechanisms of tissue hypoxia in the setting of adequate oxygen exchange from the lungs to the blood are discussed. An algorithm is proposed for diagnosing patients who present with hypoxia.