Aspirin is the most widely used medication in the world and a perfect example of a medicine that bridges the divide between natural and man-made medicines. Over 2,000 years ago, Hippocrates (440-377 BC) said that the ancient Greeks used powdered willow bark to reduce fever. Subsequently, this knowledge slipped into disuse, until it was relaunched by the Rev Edward Stone (1702-1768), a country clergyman of Chipping Norton in Oxfordshire. He experimented with willow bark in relieving ague fever from malaria and distempers of some 50 people; in 1763, he communicated his †ndings to the Royal Society. He was inžuenced by an application of the so-called “doctrine of signatories”: Willow grew in damp places and, because agues and fevers were associated with damp places, too, willow might produce a medicine to treat them. In the early nineteenth century, it was found that the glycoside salicin (13.1), extracted from willow bark, relieved pain. Salicin is hydrolysed upon ingestion into glucose and salicyl alcohol, metabolised to salicylic acid. By the 1870s, salicylic acid (13.2) was being used successfully to treat fevers and pain, but gastrointestinal problems were a side effect.