Chapter 2 discusses smallpox inoculation (variolation) in the late eighteenth century. The development of a light form of the procedure, which reduced its risks and costs, made it increasingly familiar in Britain and the English-speaking world from the 1760s. The practice likewise gained new credit, as a calculated risk, in elite and enlightened circles in continental Europe. Rulers like Catherine the Great promoted the practice, recognising its potential value to the state as well as the individual. In England, the emergence of specialist inoculators seeking the commercial edge, the practice of ‘general inoculations’ in villages, and the public health risks of popular recourse to the practice in urban settings brought to light cases of individuals previously infected with cowpox being resistant to smallpox and provided the technology and incentive to explore the possible advantages of inoculating cowpox as a safe alternative. In the meantime, the rapid expansion of smallpox inoculation, not least in European colonies, provided a launching pad for the global spread of vaccination in the decade after 1800.