Fentanyl, introduced more than 50 years ago, has become the most often used opioid for intraoperative analgesia. Since the early 1990s the fentanyl patch has been available for management of chronic pain of all forms of cancer as well as the persistent, intense pain from many noncancerous maladies. More than a half dozen rapid-onset transmucosal fentanyl preparations have been developed, approved, launched, and popularized for "breakthrough" pain syndromes in the past 20 years. The purpose of this article is to describe why this opioid has become so important in the treatment of pain in modern clinical practice. The data indicate that fentanyl's popularity has occurred because it has minimal cardiovascular effects, does not result in increases in plasma histamine, is relatively short in onset of action and duration of effect, is easy and inexpensive to synthesize and prepare for the marketplace, and is now familiar to clinicians working in pain and perioperative medicine throughout the world.