Postoperative ileus (POI), a transient cessation of coordinated bowel function after surgery, is an important health care problem. The etiology of POI is multifactorial and related to both the surgical and anesthetic pathways chosen. Opioids used to manage surgical pain can exacerbate POI, delaying gastrointestinal (GI) recovery. Peripherally acting mu-opioid receptor (PAM-OR) antagonists are designed to mitigate the deleterious effects of opioids on GI motility. This new class is investigational for POI management with the goal of accelerating the recovery of upper and lower GI tract function after bowel resection. In this review, we summarize the mechanisms by which POI occurs and the role of opioids and opioid receptors in the enteric nervous system, discuss the mechanism of action of PAM-OR antagonists, and review clinical pharmacology and Phase II/III POI trial results of methylnaltrexone and alvimopan. Finally, the role of anesthesiologists in managing POI in the context of a multimodal approach is discussed.