The practice of variolation, inoculation into the skin of dried secretions from a smallpox bleb, was invented in China about 1000 years ago and spread along the silk route, reaching Asia Minor in the 17th century. Lady Mary Wortley Montague wife of the British ambassador to Constantinople, described the practice in a letter dated April 1, 1717, and imported the idea to England when she came home. By the time Jenner was a child, variolation had become popular among educated English families as a way to provide some protection against smallpox.

Jenner knew the popular belief in Gloucestershire that people who had been infected with cowpox, a mild disease acquired from cattle, did not get smallpox. He reasoned that since smallpox in mild form was transmitted by variolation, it might be possible similarly to transmit cowpox. A smallpox outbreak in 1792 gave him an opportunity to confirm this notion. In 1796 he began a courageous and unprecedented experiment – one that would now be unethical, but that has had incalculable benefit for humankind. He inoculated a boy, James Phipps, with secretions from a cowpox lesion. In succeeding months until the summer of 1798 he inoculated others, most of them children, to a total of 23. All survived unharmed, and none got smallpox.