Paracetamol (acetaminophen) is one of the most widely used of all drugs, with a wealth of experience clearly establishing it as the standard antipyretic and analgesic for mild to moderate pain states. First used clinically by von Mering in 1893, paracetamol did not appear commercially until 1950 in the United States and 1956 in Australia. During the 1960s and 1970s, increasing concern was raised about the toxicity of nonprescription analgesics, but in normal use paracetamol exhibited a consistent safety profile. Its exemplary safety record was marred by the discovery in 1966 that a major overdose could be complicated by severe and sometimes fatal liver damage. Fortunately, early treatment with N-acetylcysteine prevents liver toxicity. A turning point in the choice of pediatric analgesic came in the 1980s when aspirin was linked to Reye's syndrome. As a consequence, paracetamol became the mainstay analgesic and antipyretic for children with a subsequent reduction in the incidence of Reye's syndrome. Currently, paracetamol is a first-line choice for pain management and antipyresis in a variety of patients, including children, pregnant women, the elderly, those with osteoarthritis, simple headaches, and those with noninflammatory musculoskeletal conditions. With proper use, paracetamol seldom causes adverse events and reports of serious side effects are rare. It has a broad tolerability and is of particular value in the treatment of patients in whom nonsteroidal anti-inflammatory drugs are contraindicated such as aspirin-sensitive asthmatics and people at risk of gastrointestinal complications. In the future, a better insight into the mechanism of action of paracetamol may be gained from a fuller understanding of the cyclooxygenase enzymes. In the meantime, paracetamol may find applications in other therapeutic areas, such as the prevention of atherosclerosis via a potential antioxidant activity. In summary, although it is more than a century since the first clinical use of paracetamol, it continues to be a first-line therapy of choice in adults and children with fever and pain. In addition, current research suggests that paracetamol may have a much broader clinical utility in years to come.