As prescription opioids continue to grow in popularity, it is important for healthcare providers to understand various mechanisms, dosages, uses, and special considerations with regard to hydrocodone. The semi-synthetic mu-opioid agonist has potent effects on the central nervous system that are crucial in managing chronic pain states. While the results are inconclusive as to whether hydrocodone is more efficacious than other opioids for pain, its combination formulation used to treat cough remains a common practice. Besides the potential for addiction, opioids like hydrocodone pose complications when considering at-risk patients such as those with liver and renal impairments, pediatric patients, and pregnant or breastfeeding mothers. As the liver primarily metabolizes the drug and the kidney excretes the drug, any deficits in these organs could result in poor breakdown (possibly decreasing beneficial effects) or poor elimination (possibly increasing the amount of drug in the system at a given time). Pharmacogenetic variation in different populations can result in more rapid metabolism, liberating hydromorphone quicker with earlier onset. Additive and/or synergistic effects with other opioids, muscle relaxants, benzodiazepines, and sedatives can increase risk of overdose and death. In pediatrics, while hydrocodone prescription alone is not well studied, its combination formula is frequently given to treat moderate to severe pain. In pregnancy, hydrocodone should be avoided if possible but must be monitored closely if ever prescribed. Hydrocodone remains an interesting opioid, and the more both physicians and patients appreciate pharmacologic considerations of this common medication, the higher the probability that beneficial analgesic effects can be expected and adverse outcomes minimized. This chapter focuses on the general pharmacologic concept of hydrocodone, its mechanism of action, indications, and side effects, and elaborates on special considerations such as pharmacogenomic variation between certain populations.