- 1516, Diego Miruelo explored Tampa Bay - Florida;
- 1517, Francisco Hernández de Cordova explored southwest Florida;
- 1519, Alonso Álvarez de Pineda mapped the Gulf of Mexico coast;
- 1519, Ferdinand Magellan set sail to circumnavigate the globe;
- 1521, Ponce de León attempted a settlement near Charlotte Harbor - Florida;
- 1521, Pedro de Quejo and Francisco Gordillo landed at Winyah Bay - South Carolina;
- 1521, Hernán Cortés conquered Aztec Mexico;
- 1525, Pedro de Quejo explored Amelia Island - Florida, to Chesapeake Bay;
- 1526, de Ayllón explored the South Carolina coast and attempted the settlement of San Miguel de Gualdape near Sapelo Sound - Georgia. As Dominican friars accompanied them, historians speculate the first Catholic Mass was celebrated in what would be the United States. Freezing weather and disease killed two-thirds of the settlers, including Ayllón. Some one hundred African slaves, the first in the new world, ran off and lived with the native Guales tribe;
- 1528, Pánfilo de Narváez landed near Tampa Bay with 400 settlers. After eight years of marching through swamps, constructing rafts that shipwrecked on the Texas coast, only five survived. Juan Ortiz was a captive of the Indians for 12 years. Cabeza de Vaca and three others traveled through areas of Texas, Arizona, New Mexico, Tamaulipas, Nuevo León, Coahuila, and Sinaloa, preaching the Gospel and praying for sick natives with reports of miraculous recoveries. Indians considered Cabeza de Vaca a "faith healer" and let him travel freely. Arriving in Mexico City in 1536, he sailed back to Spain, and then in 1540, helped settle Buenas Aires, Argentina;
- 1532, Francisco Pizarro conquered Peru's Inca Empire;
- 1539, Hernando de Soto, who had helped Pizarro conquer the Inca, landed in Tampa Bay. De Soto found Juan Ortiz, who related rumors of gold in Apalachee. De Soto seized Indians as guides. crossed Georgia, South Carolina, North Carolina, the Great Smoky Mountains, Tennessee, Alabama, Mississippi, Arkansas, Missouri, Kansas, and Oklahoma, before dying in 1542 near the Mississippi;
- 1540, Francisco Vázquez de Coronado looked for the Seven Cities of Gold, exploring Mexico, Arizona, New Mexico, Texas, Oklahoma and Kansas, viewing the Grand Canyon and the Colorado River;
- 1542, Juan Rodríguez Cabrillo sailed up the coast of California;
- 1559, Tristán de Luna y Arellano attempted to settle Pensacola Bay - Florida;
- 1561, Angel de Villafañe attempted to settle Santa Elena -- Port Royal Sound - South Carolina.
This was followed by the Saint Bartholomew's Day massacre in 1572, killing as estimated 30,000 Huguenots. The young King Charles the Ninth was instigated to commit this tragedy by his mother, the queen consort Catherine
On his deathbed, Charles the Ninth exclaimed to his nurse that the screams of the massacred Huguenots rang in his ears, saying
"What blood shed! What murders! ... What evil counsel I have followed! O my God, forgive me ... I am lost! I am lost!"
He told his mother "Who but you is the cause of all of this? God's blood, you are the cause of it all!"
His mother, Catherine de Medici, coldly commented that she had a lunatic for a son.
- 1607 - English Colony of Jamestown;
- 1608 - French Colony of Quebec;
- 1620 - Pilgrim Colony of Massachusetts;
- 1624 - Dutch Colony of New Amsterdam -- New York; and
- 1638 - Swedish Colony of New Sweden -- Delaware & New Jersey.
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