Complications after major surgery are a leading cause of morbidity and mortality. The etiology of postoperative complications is complex, but poor cardiorespiratory reserve appears to be a key factor. There is increasing interest in the use of central and mixed venous oxygen saturation to guide therapeutic interventions during the perioperative period. However, a detailed understanding of the physiologic principles of venous oximetry is essential for safe and effective use in clinical practice. Venous oxygen saturation reflects the balance between global oxygen delivery and oxygen consumption, which may be affected by a wide range of factors during the perioperative period. The purpose of this article is to describe the physiology and measurement of mixed and central venous oxygen saturation and to explore the findings of clinical investigations of their use in perioperative care.