PURPOSE Enhanced Recovery After Surgery (ERAS) programs have increasingly attracted the attention of clinicians who are intent on minimizing postoperative morbidity, decreasing variability in surgical care, and containing hospital costs. The purpose of this review is to discuss the relevant pathophysiology of the surgical stress response and its associated mechanisms that regulate important metabolic changes. PRINCIPAL FINDINGS The combination of hormonal release and various inflammatory responses inherent in the stress response to surgery contributes to a state of insulin resistance that represents one of the main pathogenic factors modulating perioperative outcome. The consequence of a decrease in insulin sensitivity is a significant change in protein and glucose metabolism characterized by an increase in the production of endogenous hepatic glucose, a decrease in the uptake of peripheral glucose, and an increase in the breakdown of protein. Muscle is the main tissue for uptake of insulin-mediated glucose, and consequent with the reduced activation of a specific glucose transporter protein (GLUT 4), glucose cannot be transported into the muscle cells. Consequently, breakdown of muscle protein, also related to insulin resistance, occurs to supply amino acids for gluconeogenesis, thus leading to the overall loss of lean muscle tissue. Besides the metabolic changes associated with the surgical insult, pain, relative perioperative starvation, and poor mobilization further contribute to a loss of insulin sensitivity and an increased catabolic state. Many of the ERAS elements that are implemented, including perioperative feeding, epidural analgesia, and minimally invasive surgery, modulate the stress response, promote insulin sensitivity, and attenuate the breakdown of protein. CONCLUSIONS The implementation of a targeted ERAS program has been shown to modulate perioperative insulin sensitivity, thus improving postoperative outcomes and accelerating the return of baseline function.