Opioid-induced bowel dysfunction is a distressing condition that may persist indefinitely in the clinical setting. As we understand more about normal gastrointestinal (GI) physiology, we are also beginning to understand more fully how opioids cause bowel dysfunction. Current therapeutic interventions for opioid-induced bowel dysfunction can be burdensome and sometimes lack efficacy. Systemic opioid antagonists administered orally can induce laxation, but can unpredictably induce systemic or local GI tract withdrawal symptoms. Two new investigational agents, alvimopan and methylnaltrexone, are peripherally acting opioid antagonists that do not cross the blood-brain barrier. Studies to date show promise that these agents may relieve opioid-induced bowel dysfunction in a well-tolerated manner without reversing central analgesia.