Pain remains a highly prevalent problem for patients with cancer and typically falls into one of 3 types: visceral, somatic, and neuropathic. A mechanistic, pathophysiologic approach to pain management involves a good assessment of the type of pain, followed by tailoring of the treatment based on the diagnosis. This pain management strategy can provide rapid pain control with a lower incidence of complications and side effects than other methods. Furthermore, pharmacogenetics may play an important role in individualizing therapies in the future, but for now this type of data offers explanations for phenomena commonly observed in clinical practice, such as (1) differences in individual analgesic and side-effect responses to various opioid agents, (2) incomplete cross-tolerance seen when switching between μ opioid analgesics, and (3) why opioid rotation can be beneficial for patients after an opioid therapy loses efficacy or becomes associated with intolerable side effects. Especially for difficult-to-manage pain patients, additions to the opioid analgesic armamentarium can potentially better individualize pain management, and provide another option to be used for opioid rotation. Among the most recent Food and Drug Administration–approved opioid analgesics for acute pain and persistent pain are oral immediate-release and extended-release formulations of oxymorphone, whereas for breakthrough pain, the ultrarapid-acting opioid, fentanyl effervescent buccal tablets, has newly been developed and indicated within the United States.