Intolerable side effects contribute to poor outcomes among patients managed with opioids, and negotiating these side effects remains an important clinical challenge. Evidence-based approaches to minimizing the side-effect burden from opioids compiled from the literature, and including clinical practice recommendations, focus on (1) reducing the doses of systemic opioids, (2) managing the adverse symptoms of opioids, (3) integrating opioid rotation, and (4) changing the route of administration. These broad strategies, and specific recommendations for individual side effects of opioids, including those that often go unrecognized within the following organ systems: neurologic, cardiopulmonary, gastrointestinal, urologic, endocrinologic, dermatologic, and immunologic, are considered herein. In addition, specific patient populations, opioid metabolites, and clearance issues are considered. In particular, novel medications and better alternatives to preexisting treatments for specific opioid side effects, such as peripheral opioid antagonists, may ameliorate the management of patients taking long-term opioid therapies.