Pain management in patients with cancer remains suboptimal. Breakthrough pain (BTP) is characterized by abrupt onset of severe pain in a background of otherwise stable managed pain and presents a substantial burden to patients, as it disrupts activities and quality of life. Rapid-onset opioids (ROOs), with an appropriate onset and duration of effect, provide new options for effective and well-tolerated management of BTP. All currently available ROOs are various formulations of transmucosal immediate-release fentanyl (TIRF) and, although they were originally developed and approved for use in children before painful procedures, are only approved for use in opioid-tolerant adult patients with cancer and BTP. The formulation options include oral lozenge, buccal tablet, buccal film, sublingual tablet, nasal spray, and a sublingual spray; each has practical considerations that vary with the product and route of administration. All have the common advantage of rapid entry into the systemic circulation via transmucosal absorption, avoiding hepatic and intestinal first-pass metabolism and allowing a rapid onset of action that rivals intravenous injections. Rapid onset and short duration of action allow good patient control of analgesia. The pharmacokinetic and analgesic properties of ROOs may allow reduction of the total opioid burden and associated adverse effects, while still providing effective pain relief. The shared TIRF risk evaluation and mitigation strategy program implemented in March 2012 has simplified enrollment and administration of these products to help mitigate the risks of abuse and misuse and to help ensure safe use in patients with cancer suffering from BTP.