The treatment of patients with acute and chronic pain not attributed to cancer or end-of-life conditions is a challenge for many clinicians. Although CDC guidelines that focus on the primary care setting have provided critical recommendations, evidence-based guidance is lacking on optimal duration of opioid treatment for postoperative and acute care in specialty settings. Over the last 2 decades, the liberal use of opioids has resulted in many unintended consequences, including dependence and abuse, illicit distribution of legally and illegally prescribed opioid medication, progression to IV heroin and an epidemic of overdoses, and most recently an increase in the incidence of HIV among patients sharing syringes, frequently in communities with historically low HIV rates. This article analyzes these complex issues and proposes strategies to help clinicians improve patient care through education and responsible prescribing.