The first protection against smallpox, a disease known already in old China and India, consisted in rubbing infectious material from smallpox patients into the scratched skin of children. Lady Montagu brought this method from Turkey to England in 1721. This "variolation", however dangerous, was adopted in Europe during the eighteenth century mainly by the aristocracy. But it was Edward Jenner (1749-1823) who in 1796 used cowpox to protect against smallpox without the risk of acquiring the disease. During more than 60 years the "vaccination" was carried out from "arm to arm" with a certain risk of transmission of syphilis. From 1864 on the vaccine was mainly produced on cows to avoid this risk. The WHO managed in 1978 to eliminate smallpox from the planet by vaccination. The smallpox outbreaks, the inoculation, the vaccination and the production of cowpox vaccine in Luxembourg are described.