The metabolism of opioids is critical to consider for multiple reasons. The most commonly prescribed opioid agents often have metabolites that are active and are the source of both analgesic activity and an increased incidence of adverse events. Many opioids are metabolized by cytochrome P450 enzymes. Polymorphisms in cytochrome P450 genes and inhibition or induction of cytochrome P450 enzymes by coadministered drugs may significantly impact the systemic concentration of opioids and their metabolites and the associated efficacy or adverse events. This is a narrative review of the metabolism of various opioids that will highlight the impact of their active metabolites, and the potential impact of cytochrome P450 activity on analgesic activity. An understanding of "opioid metabolic machinery," cytochrome P450 activity, and drug-drug interactions in the context of opioid selection may benefit clinicians and patients alike. A greater appreciation of the metabolism of commonly prescribed opioid analgesics and the impact of their active metabolites on efficacy and safety may aid prescribers in tailoring care for optimal outcomes.