At its most inclusive, in the United States the region cuts a wide swath from the Twin Cities of Minneapolis–Saint Paul in Minnesota in the west, south to St. Louis and Louisville, Kentucky, and east to Rochester, New York; in Canada, it continues northeasterly to Quebec City.

Within this broad region, there is a core area of more continual urban development that includes Chicago, Milwaukee, Grand Rapids, South Bend, Detroit–Windsor, Cincinnati, Columbus, Cleveland, Toledo, Pittsburgh, Buffalo, Rochester, Toronto, Ottawa, Montreal, and the metropolitan areas between these.

[4] In the 1960s and 1970s, urban planner and architect Constantinos Doxiadis wrote books, studies, and reports about the growth potential of the Great Lakes Megalopolis.

[8][9][10] The America 2050 project identified 11 Megaregions of the United States, including the Great Lakes Megalopolis.

Most of the states have joined the provinces in forming the Conference of Great Lakes and St. Lawrence Governors and Premiers to coordinate economic and environmental strategies throughout most of the region.

[12] The five Great Lakes contain one-fifth of the world's surface fresh water and have a combined shoreline of 10,210 miles (17,017 km).

The Great Lakes Megalopolis includes the following major inter-urban corridors that are provided with freeway and passenger rail service in both the core and fringe areas of the mega-region.

Interstate 94 and Amtrak's Empire Builder and Borealis trains run roughly parallel from Chicago to Minneapolis/St.

Interstate 90 and Amtrak's Lake Shore Limited run approximately parallel through the core area of the megalopolis from Chicago to Cleveland via South Bend, Indiana, and Toledo, Ohio, then into the eastern fringe area comprising Buffalo and Rochester, New York.

Amtrak's Floridian provides a passenger rail link from Cleveland to Pittsburgh which is roughly paralleled by Interstate 76.

Amtrak also serves this route with the Wolverine service, between Chicago and Pontiac via Ann Arbor and Detroit.

Intermediate points along the corridor include London, Kitchener, Hamilton, St. Catharines, Toronto, Kingston, Ottawa, and Montreal.

Intermediate points include Fort Wayne, Indiana, and Lansing, Flint, and Port Huron, Michigan/Sarnia, Ontario.