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Born in Santervas, Spain, in 1460 (the date is uncertain), Ponce de Leon was a soldier fighting Muslims in southern Spain in the early 1490's. Ponce de Leon sailed on Christopher Columbus' second expedition to the Americas in 1493. Ponce de Leon did not return to Spain with Columbus; he stayed in Santo Domingo (now called the Dominican Republic).

He was appointed governor of the Dominican province of Higuey. He later heard of gold in the neighboring island of Borinquen (now called Puerto Rico) and brutally conquered the island, claiming it for Spain. He was then appointed governor of this island. Due to his extreme brutality to Native Americans, he was removed from office in 1511.

Ponce de Leon was then given the right to find and take the island of Bimini (in the Bahamas); he was searching for riches and the fountain of youth (a legendary spring that gave people eternal life and health). He sailed from Puerto Rico on March 3, 1513, with three ships, the Santa Maria, the Santiago, and the San Cristobal, and about 200 men. After stops at Grand Turk Island and San Salvador, they reached the east coast of Florida (St. Augustine) in April 1513. Ponce de Leon named the land "Pascua de Florida" (feast of flowers) because they first spotted land on April 2, 1513, Palm Sunday. He then claimed the land for Spain.

They left on April 8, heading south in the warm current now known as the Gulf Stream. This oceanic current would become very important for Spanish trips from Europe to America. On the return trip, a fight broke out between Ponce de Leon's men and Native Americans in southern Florida. They sailed to Cuba, then headed north, again trying to find Bimini (but instead, finding Andros Island).

After returning to Puerto Rico, Ponce de Leon resumed fighting with the Native Americans (putting down their rebellions against Spanish rule). He returned to Spain and was named a Captain General by the King of Spain on September 27, 1514, and again sailed to Puerto Rico to search for the elusive Bimini.

His last expedition was another search for Bimini in 1521. His force of 200 men landed on the west coast of Florida, but were met by Native American warriors, who wounded many of the men with arrows, including Ponce de Leon. Ponce de Leon later died in Havana, Cuba, from this wound (in July, 1521). He is buried in San Juan, Puerto Rico.