This is the first disease to be completely eradicated from nature. It is also the least understood and most destructive disease in history. It is part of the orthopoxvirus genus which include cowpox, rabbitpox, monkeypox, amelpox, but not chickenpox (which is caused by the varicella virus)

One droplet of exhaled moisture from an infected person contains a thousand more viruses than needed to infect someone.

The first recorded attack was in ancient Egypt. The last recorded attack was in 1977. There was possible signs of smallpox rash on the mummy of Rameses V who died in 1156 B.C. The Roman Empire lost over 1/3 of their subjects in certain areas during a 15-year epidemic beginning 165 A.D. It decimated the indigenous population in America. Pocahontas died from it in 1617 during her trip to London. It killed Queen Marry II of England in 1694, Emperor Joseph I of Austria in 1711, King Louis XV of France in 1774, Emperor Gokwomyo of Japan in 1654, and Emperor Komei of Japan in 1867. George Washington managed to survive an attack after visiting Barbados in 1751, but it left him scarred. 1/3 of the population of Iceland died in 1707.

The term "smallpox" was first used in Englihs in the 16th century as a translation of the French term la petite vérole (vérole means pox).

1714, Greek physician Emanuel Timoni published an article about preventing the disease by embedding a knife into a victim's rash and then scratching it on a healthy person. This was similar to many folk techniques known in China, India, and Western Asia. After Lady Mary Wortley Montagu, wife of an English ambassador to Turkey, in 1721 allowed Gypsy women to immunize her infant son, it became popular to do so in royal families. Of course, the king first tested it on six condemned prisoners and 11 children.

In 1721, Cotton Mather heard about the practice from his slave and convinced other Congregational ministers to use the method since smallpox threatened to depopulate Boston. 6,000 residents got the disease and 900 died. Only 287 were eventually immunized of which only six died. This success was not enough to convince most people however. It was still illegal in American colonies. People were afraid it could start epidemics. Plus, there was no explanation was to why it should work. The process was counter intuitive and as a result, the public remained skeptical. Ben Franklin couldn't believe this and as a result, his four-year-old son died in the 1736 epidemic. However, John Quincy Adams was inoculated at eight in 1775. Mozart also had smallpox. Abraham Lincoln fell ill to smallpox hours after the gettysburg address. Catherine the Great of Russia, with some pressure from Voltaire , paid an English doctor 10,000 pounds and 500 pounds a year to inoculate the royal court. George Washington ordered his army to be inoculated during the revolutionary war. After that, the anti-inoculation laws were revoked.