Dating back to the ancient world, few diseases have caused as much panic and destruction as the bubonic plague. This dreaded bacterial infection typically circulates among rats and rodents, but when transmitted to humans through fleabites, it spreads rapidly through the body and often proves fatal within mere days. From a Byzantine scourge to a 19th century pandemic that spanned the globe, take a look back at six of the most infamous outbreaks of the disease once known as the “Great Mortality.”

The Plague of Justinian

Painting showing the plague in Constantinople
Painting showing the plague in Constantinople. (Credit: Walters Art Museum)

Justinian I is often credited as the most influential Byzantine emperor, but his reign also coincided with one of the first well-documented outbreaks of plague. The pandemic is believed to have originated in Africa and then spread to Europe through infected rats on merchant ships. It reached the Byzantine capital of Constantinople in 541 A.D., and was soon claiming up to 10,000 lives per day—so many that unburied bodies were eventually stacked inside buildings or left in the open. According to accounts by the ancient historian Procopius, the victims demonstrated many of the classic symptoms of bubonic plague, including sudden fever and swollen lymph nodes. Justinian himself was stricken and managed to recover, but over a third of Constantinople’s residents were not so lucky. Even after it subsided in Byzantium, the plague continued to reappear in Europe, Africa and Asia for several years, causing widespread famine and devastation. It is believed to have killed at least 25 million people, but the actual death toll may have been much higher.

The Black Death

Scene of the plague in Florence.
Scene of the plague in Florence. (Credit: DeAgostini/Getty Images)

In 1347, a virulent strain of plague invaded Europe from the East, most likely via Italian sailors returning home from Crimea. This “Black Death” would eventually spend half a decade tearing across the continent. The populations of whole towns were wiped out, and it was said that the living spent most of their time burying the dead in mass graves. “We see death coming into our midst like black smoke,” the Welsh poet Jeuan Gethin wrote, “a plague which cuts off the young, a rootless phantom which has no mercy or fair countenance.” Medieval physicians tried to combat the disease using bloodletting, lancing and other crude techniques, but with little understanding of its cause, most fell back on the belief that it was a divine punishment for their sins. Some Christians even blamed it on Jews and launched bloody pogroms. The Black Death finally subsided in the West around 1353, but not before it killed as many as 50 million people—more than half the population of Europe. While the pandemic left much of the continent in disarray, many historians also believe that the labor shortages it caused were a boon to lower class workers, who saw increased economic and social mobility.

The Italian Plague of 1629-31

Drawing of the Great Plague in Milan
Drawing of the Great Plague in Milan. (Credit: Fine Art Images/Heritage Images/Getty Images)

Even after the Black Death ended, bubonic plague continued to sporadically rear its ugly head in Europe for several centuries. One of the most calamitous outbreaks began in 1629, when troops from the Thirty Years’ War carried the infection into the Italian city of Mantua. Over the next two years, the plague snaked its way across the countryside, striking the major cities of Verona, Milan, Venice, and Florence. In Milan and Venice, city authorities quarantined the sick in “pesthouses” and burned their clothes and possessions to prevent the spread of infection. The Venetians even banished some of their plague victims to a pair of islands in a nearby lagoon. These harsh measures may have helped contain the scourge, but it still killed some 280,000 people, including over half the residents of Verona. The Republic of Venice, meanwhile, lost nearly a third of its population of 140,000. Some scholars have since argued that the outbreak may have sapped the city-state’s strength and led to its decline as a major player on the world stage.

The Great Plague of London

Drawing by William Blake of plague victims.
Drawing by William Blake of plague victims. (Credit: Fine Art Images/Heritage Images/Getty Images)

Plague laid siege to the city of London several times during the 16th and 17th centuries, most famously between 1665 and 1666. The pestilence first arose in the suburb of St. Giles-in-the-Fields, but it soon traveled into the cramped and filthy neighborhoods of the city proper. At its peak in September 1665, some 8,000 people were dying each week. The wealthy—including King Charles II—fled to the countryside, leaving the poor as the plague’s main victims. “Never did so many husbands and wives die together,” a reverend named Thomas Vincent wrote, “never did so many parents carry their children with them to the grave.” As the sickness spread, London’s authorities tried to contain the infected by quarantining them in their homes, which were marked with a red cross. Somewhere between 75,000 and 100,000 people eventually perished before the outbreak died down in 1666. Later that same year, London was visited by a second major tragedy when the Great Fire of 1666 torched much of its city center.

The Great Plague of Marseille

Painting of Marseille during the plague.
Painting of Marseille during the plague. (Credit: Robert Valette/Wikimedia Commons)

Western Europe’s last major outbreak of medieval plague began in 1720, when a “mortal distemper” seized the French port city of Marseille. The disease arrived on a merchant ship called the Grand Saint Antoine, which had picked up infected passengers during a journey to the Middle East. The vessel was quarantined, but its owner—who also happened to be Marseille’s deputy mayor—convinced health officials to let him unload its cargo. Plague-carrying rat fleas soon spread across the city, sparking an epidemic. People died by the thousands, and the piles of bodies on the streets grew so large that convicts were conscripted to dispose of them. In nearby Provence, “plague walls” were even built to try to and contain the infection, but it still spilled over into southern France before finally disappearing in 1722. By then, it had killed roughly 100,000 people.

The Third Plague Pandemic

People in quarantine in Karachi during the outbreak.
People in quarantine in Karachi during the outbreak. (Credit: Wellcome Library, London/Creative Commons CC BY 4.0)

The first two major plague pandemics began with the Plague of Justinian and the Black Death. The most recent, the so-called “Third Pandemic,” erupted in 1855 in the Chinese province of Yunnan. The disease traversed the globe over the next several decades, and by the beginning of the 20th century, infected rats traveling on steamships had carried it to all six inhabited continents. The worldwide outbreak would eventually claim some 15 million lives before petering out in the 1950s. Most of the devastation took place in China and India, but there were also scattered cases from South Africa to San Francisco. Despite the heavy casualties, the Third Pandemic led to several breakthroughs in doctors’ understanding of the bubonic plague. In 1894, a Hong Kong-based doctor named Alexandre Yersin identified the bacillus Yersinia pestis as the cause of the disease. A few years later, another physician finally confirmed that bites from rat fleas were the main way the infection spread to humans.