In managing pain, clinicians working with the more than 80 million people in the United States who suffer annually from serious pain face decisions about choosing the most appropriate pharmacologic agent, to contemplating nonpharmacologic modalities. This article focuses on opioid use for pain management, their risks of toxicity and addiction, adverse reactions, undertreatment for fear of addiction, and integration of novel diagnostics, such as the pharmacogenetic biomarkers CYP2D6 and OPRM1 as holding promise for assessing a patient's risk of adverse events or likelihood of efficacy. Incorporation of such biomarkers is emerging on the forefront of personalized medicine, and has the potential to dramatically improve the utility and efficacy of both current and future pain management strategies.