The eighth winter storm of the season is forecast to blanket nearly one-third of the country, from the Colorado Rockies to New England.
The monster winter storm could be the biggest many cities have seen in years. Blizzard warnings have been set in seven states
Craig Fugate, the head of the Federal Emergency Management Agency or FEMA, said his agency is preparing to react to the storm as if it were an approaching hurricane.
Cities including St. Louis, Kansas City and Milwaukee could be hardest hit, with expected midweek snowfall totals of up to 2 feet and drifts piled 5 to 10 feet. The city of Chicago has also made preparations for what could be one of the worst storms in its history.
If the Windy City is hit by the storm, it is predicted it would be the city's third-largest snowstorm, surpassed only by the 21.6 inches received in 1999 and the 23 inches of snow that fell in 1967.
"I'm looking forward to it. I'm a school teacher, and we'll probably get a snow day - and it'll be the first time in a couple of years," said Katy Berman, 58, of the Chicago suburb of Des Plaines, Ill. "It doesn't faze me as long as I'm home."
Meanwhile, airlines have canceled thousands of flights. School districts, universities and legislatures have also closed in preparation of the storm's arrival.
Missouri Gov. Jay Nixon declared a state of emergency and activated 600 members of the National Guard.
Drivers were already sliding off slick roads even before the worst of the storm had arrived, with deadly accidents reported in Minnesota and Kansas.