Storm warnings have already been declared for Puerto Rico and parts of the US Virgin Islands
Haiti and the Dominican Republic are braced for a battering as Tropical Storm Isaac approaches Hispaniola, the island shared by the two countries.
Some 400,000 Haitians still living in makeshift camps after a deadly earthquake in 2010 are "amongst the most vulnerable", aid groups warn.
Isaac could have become a hurricane by the time it is due to hit the island later on Friday, meteorologists say.
It will then move on to Cuba and the southern US by the weekend.
The storm could pose a potential threat to Florida during the US Republican National Convention.
Disease warningAt 00:00 GMT, Isaac - with gusts of winds of 75km/h (45mph) - was about 340km (211 miles) south-east of the Dominican Republic's capital, Santo Domingo, the Miami-based US National Hurricane Center said.
The storm could unleash up to 20 inches (51cm) of rain when it makes landfall on the island.
"These rains could cause life-threatening flash floods and mudslides," the NHC warned.
In Haiti, people living in the makeshift squatter camps were "amongst the move vulnerable, should the storm hit the city," humanitarian group World Vision said.
"Without a stable sanitation system or permanent housing, heavy rain and wind can create much larger problems like disease from water contamination," the group's Haiti director Jean-Claude Mukadi was quoted as saying by the AFP news agency.
Isaac is also expected to bring rain and wind to the nearby Puerto Rico.