Opioids are considered important analgesics in the treatment armamentarium for moderate-to-severe background cancer pain. The past decade has seen clinical trials of transmucosal opioid formulations for breakthrough pain in cancer (BTPc), beginning with oral transmucosal fentanyl citrate (OTFC), followed by fentanyl buccal tablet and intranasal fentanyl spray, and most recently sublingual fentanyl tablet, fentanyl buccal soluble film, and fentanyl pectin nasal spray. During that time, enough rigorous evidence has accumulated to support the development of recommendations on treating BTPc with transmucosal formulations. This article describes the randomized controlled trials that have led to the support of the use of transmucosal fentanyl therapies for BTPc, starting in 1999 with OTFC formulations through to the end of 2011. Although oral opioids have been used for historical reasons, evidence supports the use of intravenous morphine or transmucosal fentanyl for treating BTPc, regardless of the opioid being taken to manage background pain. Furthermore, most studies have found no meaningful relationship between the effective dose of transmucosal opioid and the around-the-clock scheduled medication nor the previous rescue medication. The accumulated evidence shows that transmucosal fentanyl formulations provide a rapid effect on BTPc, with adverse events typical of opioids.