Hypoxemia is defined as a decreased oxygen partial pressure in arterial blood. This frequent clinical phenomenon can lead to tissue hypoxia and requires a prompt diagnostic approach to guide its management. Five pathophysiological mechanisms should be assessed in the presence of hypoxemia: alveolar hypoventilation, ventilation/perfusion mismatches, diffusion disorders, true shunts and a decrease in the partial pressure of inspired oxygen. In this article, we synthesize the main etiologies of hypoxemia based on respiratory pathophysiology and suggest a diagnostic approach for its evaluation.