Surgery represents a major stressor that disrupts homeostasis and can lead to loss of body cell mass. Integrated, multidisciplinary medical strategies, including enhanced recovery programs and perioperative nutrition support, can mitigate the surgically induced metabolic response, promoting optimal patient recovery following major surgery. Clinical therapies should identify those who are poorly nourished before surgery and aim to attenuate catabolism while preserving the processes that promote recovery and immunoprotection after surgery. This review will address the impact of surgery on intermediary metabolism and describe the clinical consequences that ensue. It will also focus on the role of perioperative nutrition, including preoperative nutrition risk, carbohydrate loading, and early initiation of oral feeding (centered on macronutrients) in modulating surgical stress, as well as highlight the contribution of the anesthesiologist to nutritional care. Emerging therapeutic concepts such as preoperative glycemic control and prehabilitation will be discussed.