Already today, Isaac had started to blast parts of the island of Hispaniola - shared by Haiti and the Dominican Republic - with winds that are expected to reach 50 to 60 m.p.h. Downpours also could dump nearly 2 feet of rain in places.
"That kind of rain is going to cause some life-threatening flash floods and mudslides," Dennis Feltgen, a spokesman for the Hurricane Center in Miami, told The Associated Press.
Nearly 400,000 people are still living in makeshift tent cities in Haiti, more than two years after a 7.0 magnitude earthquake devastated the region.
Aid workers today made a frantic last-minute effort to warn refugees, many of whom did not know a massive storm was on the way.
"The flimsier of these tents will be the first to go like kites into the sky," said Bill Horan of the nonprofit group Operation Blessing International. "There'll be people screaming, children terrorized."
In addition to fears of flash flooding, those in the area were concerned about the spread of disease.
And in the Keys, locals were stocking up on supplies to brace for the first major storm to approach Key West in seven years. Isaac, said to be twice the size of a typical hurricane, is now just 48 hours out.
In Miami, big retailers were sold out of water and people along the Keys were installing hurricane shutters and tying up boats.
Many tourists in the Keys told ABC News they intended to stay through the storm. Monroe county officials said Friday that since Isaac should still be a tropical storm when it reaches the Keys, they had decided not to issue a visitor evacuation. Schools and government offices, however, will be closed Monday.
Isaac, which was originally feared to be headed toward the GOP convention in Tampa, will now likely bring heavy rain there with winds of up to 50 mph, but not the hurricane-force wind, rain and flooding that was originally predicted.
ABC News' Alex Perez in Haiti and Matt Gutman in Florida contributed to this piece.