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Spanish explorer Ponce de León gave the Dry Tortugas their name on his first visit in 1513. The name is the second oldest surviving European place-name in the US.^[3] They were given the name Las Tortugas (The Turtles) due to 170 sea turtles taken on the islands and shoals by de León's men. Soon afterward, the word "Dry" was added to the name, to indicate to mariners the islands' lack of springs.^[4]

In 1742 HMS Tyger wrecked in the Dry Tortugas. The stranded crew lived on Garden Key for 56 days, and fought a battle with a Spanish sloop, before sailing to Jamaica in several boats.^[5]

The United States government never completed Fort Jefferson after 30 years on Garden Key, and this bastion remained in Union hands throughout the Civil War. It later was used as a prison until abandoned in 1874. Dr. Samuel Mudd, famous for being the doctor who treated John Wilkes Booth in the wake of the Lincoln assassination, was imprisoned here until early 1869. During the 1880s, the Navy established a base in the Dry Tortugas, and it subsequently set up a coaling (refueling) and a wireless (radio) station there as well. During World War I, a seaplane base was established in the islands, but it was abandoned soon thereafter.

From 1903 until 1939 the Carnegie Institution of Washington operated the Marine Biology Laboratory on Loggerhead Key which "...quickly became the best-equipped marine biological station in the tropical world.” Through the years, over 150 researchers used the facilities to perform a wide range of research.^[6] In June 1911 the laboratory built a vessel in Miami, Anton Dohrn, for use by researchers as well as logistics between the station and Key West.^[7] The vessel, excepting a period of World War I service with the Navy, supported the laboratory's work until closure in 1939 and donation of Anton Dohrn to the Woods Hole Oceanographic Institution.^[8]

An account of a visit to the fort at the Dry Tortugas by President Franklin D. Roosevelt and Justice-to-be Robert H. Jackson can be found in the book That Man: An Insider's Portrait of Franklin D. Roosevelt, by Robert H. Jackson, edited and introduced by John Q. Barrett (Oxford University Press, New York, 2003).

The Dry Tortugas are also rich in maritime history. In 1989 Seahawk Deep Ocean Technology explored a shipwreck believed to be part of the 1622 Spanish treasure fleet. The wreck located in 1332' (406m) of water, yielded olive jars, copper, gold, silver, glass and other cultural artifacts.^[9] On September 6, 1622, the Nuestra Señora de Atocha was driven by a severe hurricane onto a coral reef near the Dry Tortugas, about 35 miles (56 kilometers) west of Key West. Mel Fisher and his company discovered the wreck July 20, 1985. The estimated $450 million cache recovered, known as "The Atocha Motherlode," included 40 tons of gold and silver; there were some 114,000 of the Spanish silver coins known as "pieces of eight", gold coins, Colombian emeralds, gold and silver artifacts, and 1000 silver ingots.^[10] In addition to the Atocha, Fisher's company, Salvors Inc., found remains of several nearby shipwrecks, including the Atocha's sister galleon the Santa Margarita, lost in the same year, and the remains of a slave ship known as the Henrietta Marie, lost in 1700.^[11]

In August 2004, the Dry Tortugas were directly struck by Hurricane Charley. The following day, a Cessna airplane crashed into the water near the islands, killing cinematographer Neal Fredericks while he was filming scenery for the feature film CrossBones.^[12]