In the summer of 1605, the French explorer Samuel de Champlain sailed along the coast of New England, looking for a likely spot to place a colony — a place more hospitable than the upper St. Lawrence River, which he had previously explored. Halfway down the Maine coast he began to find spots with good harbors, abundant supplies of freshwater, and big spreads of cleared land. The problem was that these parcels were already occupied. The peoples there were happy to barter with him and treat his sailors to fine dinners. But none were interested in providing free real estate. A skirmish in Nauset Bay, halfway down Cape Cod, convinced Champlain that he had no hope of starting a colony in this area. Too many people already lived there.

Fifteen years later, a band of English voyagers showed up in Massachusetts. The Pilgrims were everything that Champlain was not: inexperienced, poorly supplied, and lacking in basic survival skills. Arriving on the cusp of winter, they anchored offshore, planted their metaphorical flag on some choice land, and quickly set about the business of dying en masse. Surprisingly, the Pilgrims made it through the winter; within a few years, they were prospering. Why did the land’s original inhabitants, so clear about their rejection of the French, allow the English company to stay?

Pilgrim writings provide the answer. Colonist William Bradford learned that three or four years before the Mayflower landed, shipwrecked French seamen had set up shop on Cape Cod. Unwilling to countenance a long-term foreign presence, no matter how unintended, the Indians of Nauset, Bradford recounted, “never left watching & dogging them till they got advantage, and kild them all but 3 or 4.” Even this limited mercy proved a mistake. One of the French carried a disease not known in the Americas. He bequeathed it to his captors, who passed it on to their friends and families. As the epidemic spread, the healthy fled from the sick, unwittingly carrying the disease with them to neighboring communities. All along the New England coast, the English poet-adventurer Thomas Morton reported, Indians “died in heapes, as they lay in their houses.” So many perished so quickly that the living had no time to bury the dead. Morton, who settled in Massachusetts in 1624, found native skeletons still littering the woods. The Pilgrims fared better than Champlain because they were moving into land that was now largely unoccupied.

Their story was no exception. Although Europeans had firearms, steel blades, and horses, none of which existed in the Americas, their biggest weapon was biological. By a quirk of evolutionary history, the Western Hemisphere had few epidemic diseases — no smallpox, influenza, measles, or malaria. When these illnesses hitchhiked to the Americas aboard European ships, somewhere between two-thirds and nine-tenths of the native population of the Americas died. Arguably, this is the single most powerful explanatory fact in the entire history of the Americas post-1492.

Consider the two assaults by Hernán Cortés on Mexico’s