Jared Diamond, best-selling author of Guns, Germs, and Steel, popularized the notion that European imperialism succeeded due to European advantages over other people in the areas of, well... guns, germs, and steel. As far as colonization of the Americas is concerned, though, guns and steel were all but immaterial. The germs alone were enough.
The word "conquistador" evokes memories of Cortés and Pizarro, but in truth the greatest conquistadors of the New World were smallpox and influenza—not to mention typhoid, cholera, tuberculosis, measles, scarlet fever, yellow fever, and malaria.
Every one of these diseases, endemic to the Old World, spread to the Americas after 1492 with catastrophic effects for indigenous people there. (In return, the Americas afflicted the Old World with only one major affliction—syphilis. And even that is in dispute; scientists and historians remain divided on whether the disease truly originated in the New World.)
Old World diseases—lethal enough already on their continents of origin—became exponentially more dangerous in America, where they spread as virgin-soil epidemics among native populations totally lacking in immunities to them. (In Europe and Africa, countless children died from diseases like smallpox and malaria; those who survived, however, built up antibodies that inoculated them against adult infection. Since no Native Americans had ever encountered these diseases, none built up any immunity, leaving entire populations as "virgin soil" for infection. When the diseases struck, entire communities could be felled in a matter of days.)
Virgin-soil epidemics are among the deadliest phenomena ever experienced by humankind, and the death toll of the pandemics unleashed in the Americas by the Columbian Exchange far exceeded that of history's most famous virgin-soil epidemic, Europe's Black Death (an outbreak of bubonic plague in the 1340s). The cataclysmic effects of virgin-soil epidemics struck Native American societies just as they faced the threat of European invasion, decisively reducing the natives' capability to resist colonization. (It is worth noting that devastating smallpox pandemics struck both the Aztecs and Incas just before their respective disastrous encounters with Cortés and Pizarro.)
Perhaps the most arresting evidence of the consequences of virgin-soil epidemics came from the entrada of Hernando de Soto, who led an army of conquistadors deep into the North American mainland in 1539. De Soto hoped to find gold in the country that today comprises the southeastern United States; he ended up leading more than 600 men and hundreds of livestock on a four-year wild goose chase. In the end, his mission proved to be a fiasco—two-thirds of the men, including De Soto himself, died without ever finding a trace of gold—but De Soto's expedition powerfully illustrated the destructive force of smallpox, which apparently spread from his pigs to the people of the Mississippi Valley. Before leaving, De Soto's men recorded their impressions of the Mississippian people—they found dense settlements, with large villages and cities often sited within view of each other, separated by carefully tended fields of corn. After De Soto left the country, no European returned for more than 100 years. When the French explorer La Salle canoed down the Mississippi Valley in 1682, he found very few villages, no cities, and no fields of corn, but instead a landscape almost devoid of people and overrun by buffalo (which De Soto had apparently never encountered).
In the 140 years that passed between the explorations of De Soto and La Salle, something transformed the Mississippi Valley from a densely populated Indian heartland into a virtually deserted wilderness. That something was almost certainly smallpox. The landscape encountered by La Salle was not, as he believed, a primeval wilderness, but rather an ecosystem that had recently experienced the sudden destruction of its keystone species—Indians. The buffalo wandered in because few Indians survived to hunt them.
From Canada to the Tierra del Fuego, the indigenous inhabitants of the Americas suffered similar calamities, the Columbian Exchange of diseases ravaging Indian communities and facilitating the European takeover of the hemisphere.