Called "the speckled monster," smallpox was considered "the most terrible of all the ministers of death." Because it spreads through infected saliva droplets, smallpox is easily transmitted by face-to-face contact.

Once a person is exposed to the Variola virus (the scientific name for smallpox), incubation takes about 12 days. Then fever, fatigue, head and backache set in, followed in two to three days by a prominent rash on the face, arms, and legs. Lesions form; they fill with pus and then begin to crust over, with scabs developing and falling off after a few weeks. A third of all victims die; most of those who recover are scarred, and many are left blind.

Smallpox is one of humankind's oldest and most awful diseases. It was present throughout the Old World, and particularly dangerous in crowded port cities such as London. There was no smallpox in the Americas until Europeans brought the virus to the New World. Native people had no chance to build immunity over time. Within a few decades of their first contact with Europeans, the Aztec and Inca succumbed to smallpox death at rates as high as 90%. The indigenous population of New England experienced a similarly disastrous collapse.

The English colonists tried to make the New World a haven from smallpox. Boston inspected all incoming ships; if one arrived with smallpox on board, it flew a quarantine flag and remained isolated until the disease had passed. People afflicted with smallpox were sent to stay — and often die — on Spectacle Island in Boston Harbor, safely distant from the city's population. However, even with these precautions, there was usually a smallpox outbreak every 12 years; each time, patients either survived and acquired immunity or they died.

An epidemic occurred "on schedule" in 1702 and then, for some unknown reason, not again in Boston for 19 years. As more and more children grew to maturity without being exposed to the pox, Bostonians knew that when the disease did return, it would be more devastating than ever before.

Cotton Mather, the minister famous for his role in the witchcraft trials had watched three of his children nearly die in earlier epidemics. In 1706 he acquired an enslaved man named Onesimus. This African-born man had no fear of smallpox. In his homeland, he told Mather, a little pus from an infected person was inserted into a cut made in the skin of a healthy person. The healthy person usually got a mild case of the disease and soon recovered; exposure to smallpox later in life had no ill effect.

Other enslaved Africans told similar stories, and Rev. Mather became as confident of the safety and success of this operation as he was "that there are Lions in Africa." A decade later, Mather read two different accounts from doctors in Turkey who had discovered that the same method was followed in the eastern Mediterranean. He was convinced that the practice was sound.

In the spring of 1721, a group of sailors brought smallpox with them when they came ashore in Boston. As soon as the first cases appeared, the town took dramatic measures to isolate the infected men, but it was too late. By May the city was in the grip of a virulent epidemic.

Mather tried to tell doctors what he knew about inoculation; all but one ignored him. The surgeon Zabdiel Boylston found Mather persuasive and decided to inoculate his own son and two of his slaves.

Controversy erupted the minute word got out. Although the Boston clergy lined up behind Mather and Boylston, the town's physicians and the common people thought the practice barbarous. They called his technique "poisoning" and urged the authorities to charge the doctor with murder if the experiment failed.

James Franklin's newspaper The Courant began publishing attacks on those who supported inoculation. The town's ministers found themselves accused of trying to subvert the will of God. Smallpox, people claimed, "is a judgment of God on the sins of the people, and to avert it is but to provoke him more." Actions as well as words were used to stop the inoculators. Cotton Mather's house was firebombed; Zabdiel Boylston was unable to leave his farm lest he be assaulted. The selectman passed an ordinance prohibiting inoculation in the city.

When news spread that Boylston's son and slaves had fully recovered, people began to defy the ban, seeking out the doctor to get inoculated. By the time the epidemic subsided, Zabdiel Boylston had inoculated 248 people. The procedure was grueling but 98% of his patients survived, compared to 85% of the non-inoculated.

Cotton Mather published the results. Swayed partly by Mather's report and partly by similarly successful experiments in England, in 1722 the British royal family chose to be inoculated — a decision that helped win acceptance for the practice.

New England was slower to adopt inoculation than other regions. Most towns relied on strict quarantines and banned inoculation except during epidemics. Even when inoculation was permitted, the relatively high cost limited access. The disease continued to maim and kill. Over 100,000 people died during a smallpox epidemic that spread throughout North America from 1775 to 1782, coinciding with (and playing a role in) the War for Independence.

And this was by no means the last epidemic. During another outbreak in Boston in 1792, 30% of the afflicted died. The beginning of the end came in 1796 when the English physician Edward Jenner developed the first vaccine that used cowpox; this represented a huge improvement over inoculation with the smallpox virus since when humans contact cowpox, it is a far milder disease than smallpox. It was, one historian wrote, "as if an Angel's trumpet had sounded over the earth."

In 1979 after a decades-long international campaign, the World Health Organization announced a major public health success: the eradication of smallpox.