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Acute and chronic pain affects more Americans than heart disease, diabetes, and cancer combined. Conservative estimates suggest the total economic cost of pain in the United States is $600 billion, and more than half of this cost is due to lost productivity, such as absenteeism, presenteeism, and turnover. In addition, an escalating opioid epidemic in the United States and abroad spurred by a lack of safe and effective pain management has magnified challenges to address pain in the workforce, particularly the military. Thus, it is imperative to investigate the organizational antecedents and consequences of pain and prescription opioid misuse (POM). This chapter provides a brief introduction to pain processing and the biopsychosocial model of pain, emphasizing the relationship between stress, emotional well-being, and pain in the military workforce. We review personal and organizational risk and protective factors for pain, such as post-traumatic stress disorder, optimism, perceived organizational support, and job strain. Further, we discuss the potential adverse impact of pain on organizational outcomes, the rise of POM in military personnel, and risk factors for POM in civilian and military populations. Lastly, we propose potential organizational interventions to mitigate pain and provide the future directions for work, stress, and pain research.