The opioid epidemic is America's public health crisis. In 2015, 12.5 million people in the United States older than 12 years reported misusing prescription opioids and 2 million people reported having prescription opioid use disorder, up from 11.5 million and 1.9 million, respectively, in 2014. 1 No matter the causes for such a rapid rise, the enormous risk of morbidity and death associated with opioid use and abuse cannot be understated. Drug overdose is the leading cause of death for Americans younger than 50 years, killing more people than guns or motor vehicle accidents. 2 In 2015, 33,091 people-90 people per day-died of opioid overdose in the United States, and nearly onehalf of these deaths were attributed to overdose of prescribed opioids. 3,4 President Donald Trump has declared the opioid epidemic a national public health emergency, which anticipates enhanced efforts to identify those in need and to create effective treatment and prevention programs. 5 The accelerated use, abuse, and lethality associated with the opioid epidemic together with the national interest in ameliorating its deathly toll brings to light the need for understanding the who, how, and why of this epidemic. The knowledge that men and women have different reasons and patterns of substance use and abuse could be the critical, lifesaving key toward change. The medical and scientific research community is beginning to understand the vast impact patient sex and gender has on health and illness. The appreciation that men and women can differ in disease pathophysiology, symptom presentation, treatment response, and disease outcome can facilitate improved health outcomes through tailored treatments. A greater understanding of how men and women may differ in the sociocultural factors that contribute to drug use, predilection for the progression from initiation to addiction, opioid use disorder screening challenges, and responses to intervention will become valued pieces of the puzzle toward overcoming the challenges in designing effective strategies in prevention and treatment of opioid addiction. This Specialty Update in Clinical Therapeutics is dedicated to The Opioid Epidemic: Overcoming Challenges by Using a Sex and Gender Lens. We are pleased to highlight research that provides a deeper understanding of sexand gender-based differences that contribute to the epidemic of opioid use disorders. In their literature-based commentary, Dr. Andrew Koons and colleagues 6 emphasize the need to include women in research studies of pain experience and opioid abuse. The authors caution that most of our knowledge and understanding of the experience of pain and the factors that lead to opioid abuse have been generated through research dominated by male animal and human models. 7 Their thorough review of recent evidence underscores sex and gender differences in the experience of pain, rate and risk factors for opioid use disorder, and response to treatment that can assist health care providers in opioid prescribing stewardship. Gender Differences in Pain ...