The Keys are regularly threatened by tropical storms and hurricanes, leading to evacuations to the mainland. Untouched for many years, a carefree attitude led many residents to view mandatory evacuations as voluntary and voluntary evacuation orders as "nothing at all". The attitude proved dangerous when Hurricane Georges, after tearing up much of the Caribbean, caused damage and extensive flooding in the Lower Keys in 1998, before making landfall in Mississippi. In 2005, Hurricanes Katrina, Wilma, and Rita affected the Keys, causing widespread damage and flooding.

Tropical cyclones present special dangers and challenges to the entire Keys. Because no area of the islands is more than 20 feet above sea level (and many are only a few feet elevation), and water surrounds the islands, nearly every neighborhood is subject to devastating flooding as well as hurricane winds. In response, many homes in the Keys are built on concrete stilts with the first floor being not legally habitable and enclosed by breakaway walls that are not strongly attached to the rest of the house. Nonetheless, Monroe county, as reported in the Federal Register, has estimated that there are between 8,000 and 12,000 illegal enclosures inhabited by people.

Because of the threat from storm surge, evacuations are routinely ordered when the National Weather Service issues a hurricane watch or warning, and are sometimes ordered for a tropical storm warning. Evacuation of the Keys depends on causeways, bridges and the two-lane highway to the mainland. Time estimates for evacuating the entire Keys range from 12 to 24 hours. Evacuation estimates are significant in emergency planning, of course, but also because they are a factor in local and state regulations for controlling development. The building permit allocation was increased in 2005 when local governments reduced estimates for evacuation.

In the active hurricane seasons of 2004 and 2005, the Keys were under mandatory evacuation orders several times. In August, 2004, Hurricane Charley passed about 70 miles west of Key West, bringing tropical storm winds to the lower keys. The lower keys were evacuated in preparation for Hurricane Ivan in September, 2004 and Hurricane Dennis in July, 2005, but neither hurricane came close enough to the Keys to do much damage. Hurricane Katrina, which went on to devastate parts of Louisiana and Mississippi, moved through south Florida in August, 2005 and tracked southwest past Key West, causing minor damage and flooding. Hurricane Rita, which went on to destroy parts of Louisiana and Texas, grew from a tropical storm to a Category 2 hurricane as it moved westward from the Bahamas, passing south of Key West and causing damage and surge flooding as far north as Key Largo.

In 1935, new bridges were under construction to connect a highway through the entire Keys. Hundreds of World War I veterans working on the roadway as part of a government relief program were housed in unreinforced buildings in three construction camps in the Upper Keys. When the evacuation train failed to reach the camps before the storm, more than 200 veterans perished. Their deaths caused anger and charges of mismanagement that led to a congressional investigation. The storm also ended the 23-year run of the Overseas Railway. The damaged tracks were never rebuilt, and the Overseas Highway (U.S. Highway 1) replaced the railroad as the main transportation route from Miami to Key West.

With Wilma approaching in October of 2005, the entire island chain was under a mandatory evacuation order. Business owners were forced to close their businesses. After the hurricane had passed, a storm surge from the backwash of up to 8' from the Gulf of Mexico completely inundated a large portion of the Keys from Long Key to Key West. Low-lying areas of Key West and the middle and lower Keys, were under up to 3' of water from the storm surge. Sixty percent homes in Key West were flooded. Much of the originally settled "oldtown," such as the Solares Hill and cemetery areas, did not flood due to their higher elevations of 12-16'

The surge destroyed tens of thousands cars throughout the middle and lower Keys, and many houses were flooded with 1-2 feet of sea water. A local newspaper referred to Key West and the lower Keys as a "car graveyard." The peak of the storm surge occurred when the eye of Wilma had already passed over the Naples area and the sustained winds during the surge were less than 40 mph. Most Keys residents thought the storm was over and that the keys were once again spared. Many left their homes to in their cars and got caught in the rising waters or returned home to find their homes flooded.

The storm destroyed many piers, marinas, and boats. It breached the shark tank at the Key West Aquarium, freeing its sharks. The Overseas Highway and all side roads from Grassy Key to Key West were filled with contents of entire homes, businesses and motels that were damaged from the flood waters. Damage postponed the famous Halloween Fantasy Fest until December.

The previous big hurricane was Hurricane Georges a Category 2, in September 1998. The storm damaged many of the houseboats along Houseboat in Key West, as it slowed down and moved westward with the eye right off the coast of Key West. In March 2006, the NOAA opened its National Weather Forecasting building in the Truman Annex. The building is designed to withstand a Category 5 hurricane and its storm surge.