Smallpox is believed to have first infected humans around the time of the earliest agricultural settlements some 12,000 years ago. No surviving evidence of it, however, predates the so-called New Kingdom of Egypt, which lasted from about 1570 B.C. to 1085 B.C.

A few mummies from that era contain familiar-looking skin lesions. Ramses V, for example, who ruled for roughly four years in the 12th century B.C., looks to have had the raised bumps on his face and body for which smallpox is named (it’s derived from the Latin word for “spotted”).

Moreover, an ancient Egyptian papyrus scroll briefly describes what could be smallpox, as do Hittite clay tablets. The Hittites, who lived in the Middle East, even accused the Egyptians of infecting them during a war between the two empires.

Many historians speculate that smallpox likewise brought about the devastating Plague of Athens in 430 B.C. and the Antonine Plague of A.D. 165 to 180, the later of which killed an estimated 3.5 million to 7 million people, including Emperor Marcus Aurelius, and hastened the decline of the Roman Empire.

At any rate, it reached Europe no later than the 6th century, when a bishop in France unmistakably described its symptoms—a violent fever followed by the appearance of pustules, which, if the patient survived, eventually scabbed over and broke off. By that time, the contagious disease, caused by the variola virus, had spread all across Africa and Asia as well, prompting some cultures to worship special smallpox deities.

In the Old World, the most common form of smallpox killed perhaps 30 percent of its victims while blinding and disfiguring many others. But the effects were even worse in the Americas, which had no exposure to the virus prior to the arrival of Spanish and Portuguese conquistadors.

Tearing through the Incas before Francisco Pizarro even got there, it made the empire unstable and ripe for conquest. It also devastated the Aztecs, killing, among others, the second-to-last of their rulers. In fact, historians believe that smallpox and other European diseases reduced the indigenous population of North and South America by up to 90 percent, a blow far greater than any defeat in battle.

Recognizing its potency as a biological weapon, Lord Jeffrey Amherst, the commander-in-chief of British forces in North America during the French and Indian War, even advocated handing out smallpox-infected blankets to his Native American foes in 1763.

Knowing that no one can contract smallpox twice, survivors of the disease were often called upon to try and nurse victims back to health. Throughout much of the last millennium, this involved herbal remedies, bloodletting and exposing them to red objects.

One prominent 17th-century English doctor realized that those who could afford care actually seemed to be dying at a higher rate than those who couldn’t. Yet that didn’t stop him from telling a smallpox-infected pupil to leave the windows open, to draw the bed sheets no higher than his waist and to drink profuse quantities of beer.

Far more effective was inoculation, also called variolation, which involved taking pus or powdered scabs from patients with a mild case of the disease and inserting them into the skin or nose of susceptible, healthy people. Ideally, the healthy people would suffer only a slight infection this way and, in so doing, would develop immunity to future outbreaks.

Some people did die, but at a much lower rate than those who contracted smallpox naturally. Practiced first in Asia and Africa, variolation spread to the Ottoman Empire around 1670 and then to the rest of Europe within a few decades. Its first proponent in the present-day United States was Cotton Mather, a Puritan minister best known for vigorously supporting the Salem witch trials. Benjamin Franklin, who lost a son to smallpox, was another early American supporter.

Variolation notwithstanding, smallpox continued wreaking havoc on princes and paupers alike. In the 17th and 18th centuries, it killed several reigning European monarchs, including Habsburg Emperor Joseph I, Queen Mary II of England, Czar Peter II of Russia and King Louis XV of France, as well as an Ethiopian king, a Chinese emperor and two Japanese emperors.

Queen Elizabeth I of England and U.S. President Abraham Lincoln also apparently contracted smallpox during their time in office, though they fortuitously lived to tell the tale. Meanwhile, in Europe alone, an estimated 400,000 commoners were succumbing to smallpox annually.

Finally, in 1796, English doctor Edward Jenner performed an experiment that would, in good time, cause the virus’ downfall. By inserting pus from a milkmaid with cowpox, a disease closely related to smallpox, into the arms of a healthy 8-year-old boy and then variolating him to no effect, Jenner was able to conclude that a person could be protected from smallpox without having to be directly exposed to it. This was the world’s first successful vaccine, a term that Jenner himself coined. He tried to get his results published by the prestigious Royal Society, only to be told not to “promulgate such a wild idea if he valued his reputation.”

Persisting anyway, his vaccine gradually started catching on. The advantages over variolation were many. Unlike a variolated person, a vaccinated person could not spread smallpox to others. Moreover, the vaccine seldom left a rash and proved fatal in only the rarest of circumstances.

“Future generations will know by history only that the loathsome smallpox existed and by you has been extirpated,” U.S. President Thomas Jefferson wrote to Jenner in 1806. The following year, Bavaria declared vaccination mandatory, and Denmark did the same in 1810.

Because the vaccine originally had to be transferred from arm to arm, its use spread slowly. It was also much less effective in tropical countries, where the heat caused it to quickly deteriorate. Nonetheless, one country after another managed to rid itself of the disease. The last reported U.S. case came in 1949.

Spurred by two new technological advances—a heat-stable, freeze-dried vaccine and the bifurcated needle—the World Health Organization then launched a global immunization campaign in 1967 with the goal of wiping out smallpox once and for all. That year, there were 10 million to 15 million cases of smallpox and 2 million deaths, according to WHO estimates. Yet just a decade later, the number was down to zero. No one has naturally contracted the virus since a Somali hospital worker in 1977 (though a laboratory accident in England did kill someone in 1978).

After searching far and wide for any remaining trace of smallpox, the WHO’s member states passed a resolution on May 8, 1980, declaring it eradicated. “The world and all its peoples have won freedom from smallpox,” the resolution stated, adding that this “unprecedented achievement in the history of public health … demonstrated how nations working together in a common cause may further human progress.”

Today, guarded laboratories in Atlanta and Moscow hold the only known stores of the virus. Some experts say these should be destroyed, whereas others believe they should be kept around for research purposes just in case smallpox somehow remerges.