Opioid prescribing is an intricate practice that integrates medical guidelines, patient history, and goals of care. Pain tolerance varies among individuals, and treatment strategies are not a simple one-size-fits-all plug-and-play algorithm. In patients with physiological variations from which opioid prescribing recommendations are based, determining the correct prescription to adequately control pain and minimize adverse effects becomes even more convoluted. Age-related factors such as changing pharmacokinetics in the elderly population and increased susceptibility to future misuse in children must be considered when determining proper dosing. Additionally, pregnant women and those suffering from chronic conditions with limited alternative treatment options pose an increased challenge to prescribers trying to practice good opioid stewardship while remaining compassionate and proactive in pain management. Regardless of the population, all patients exposed to opioids are at risk of developing opioid use disorder and must be thoroughly counseled on correct administration and disposal of prescriptions. Therefore, all non-opioid analgesic modalities should be exhausted before opioid implementation. Personalized treatment plans are useful when assessing the unique risks for special populations. An individualized approach to opioid prescribing in special populations prioritizes optimal pain relief, limits adverse outcomes, and improves quality of life.