The first known contact by Europeans on the southeastern coast came in 1521, roughly concurrent with Cortez’s conquest of Mexico. A party of Spanish slavers, led by Francisco Cordillo, ventured to what’s now Port Royal Sound, South Carolina, from Santo Domingo in the Caribbean. Naming the area Santa Elena, he kidnapped a few Indian slaves and left, ranging as far north as the Cape Fear River in present-day North Carolina.

The first serious exploration of the coast came in 1526, when Lucas Vazquez de Ayllon and about 600 colonists made landfall at Winyah Bay in South Carolina, near present-day Georgetown. They didn’t stay long, however, immediately moving down the coast and trying to set down roots in the St. Catherine’s Sound area of modern-day Liberty County, Georgia.

That colony—called San Miguel de Gualdalpe—was the first European colony in America. (The continent’s oldest continuously occupied settlement, St. Augustine, Florida, wasn’t founded until 1565.) The colony also brought with it the seed of a future nation’s dissolution: slaves from Africa. While San Gualdalpe lasted only six weeks due to political tension and a slave uprising, conclusive artifacts from its brief life have been discovered in the area.

Hernando De Soto’s infamous, ill-fated trek of 1539–1543 from Florida through southwest Georgia to Alabama (where De Soto died of a fever after four years of atrocities against any Indians in his path) did not find the gold he anticipated, nor did it enter the Charleston and Savannah coastal region dealt with in this travel guide. But De Soto’s legacy was indeed soon felt there and throughout the Southeast, in the form of various diseases for which the Mississippian tribes had no immunity whatsoever: smallpox, typhus, influenza, measles, yellow fever, whooping cough, diphtheria, tuberculosis, and bubonic plague.

While the cruelties of the Spanish certainly took their toll, far more damaging were these deadly diseases to a population totally unprepared for them. Within a few years, the Mississippian people—already in a state of internal decline—were losing huge percentages of their population to disease, echoing what had already happened on a massive scale to the indigenous tribes of the Caribbean after Christopher Columbus’s expeditions.

As the viruses they introduced ran rampant, the Europeans themselves stayed away for a couple of decades after the ignominious end of De Soto’s fruitless quest. During that quarter-century, the once-proud Mississippian culture continued to disintegrate, dwindling into a shadow of its former greatness. In all, disease would claim the lives of at least 80 percent of all indigenous inhabitants of the western hemisphere.