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The Midwest region today refers not only to States created from the Northwest Ordinance, but also may include states between the Appalachian Mountains to the Rocky Mountains and north of the Ohio River.

The region's largest city is Chicago, the nation's third largest city, though the cities of Cleveland, Indianapolis, Detroit, St. Louis, Cincinnati, Milwaukee, and Minneapolis, are also economically important. Those cities and the farms of Kansas and Iowa loom large in any imaginative description of the Midwestern soul.
Because The Northwest Ordinance region, comprising the heart of the Midwest, was the first large region of the United States which prohibited slavery (the Northeastern states emancipated slaves four decades into the 19th century), the region remains culturally apart from the country and proud of its free pioneer heritage. The regional southern boundary was the Ohio River, the border of freedom and slavery in American history and literature (See: Uncle Tom's Cabin, by Harriet Beecher Stowe; Beloved, by Toni Morrison).

The region was shaped by freedom from slavery, pioneer spirit, intellectual stimulation in one-room free public schools, and democratic feeling brought with Revolutionary War veterans, Protestant faiths and experimentation, and agricultural wealth disbursed by the Ohio River riverboats, flatboats, canal boats, and railroads. The canals in Ohio and Indiana opened so much of the Midwestern agriculture that it launched the world's greatest population and economic boom foreshadowing later "emerging markets". The commodities that the Midwest funneled into the Erie Canal down the Ohio River led to the great wealth of New York City, which overtook Boston and Philadelphia. New York State would proudly boast of its "Inland empire" — the Midwest — and would become known as the Empire State. The Midwest was predominantly rural at the time of the Civil War, dotted with small farms across Ohio, Indiana and Illinois, but industrialization, immigration, and urbanization fed the Industrial Revolution, and the heart of industrial progress became the Great Lakes states of the Midwest. German, Scandinavian, Slavic and African American immigration into the Midwest continued to bolster the population there in the 19th and 20th centuries, though generally the Midwest remains a predominantly diverse, Protestant region, while the Coasts are predominantly Catholic and the South predominantly Southern Baptist.

Midwestern or Heartland influence is felt in Pittsburgh (an old pioneer town), West Virginia (which seceded from Virginia), Louisville (an industrial city on the Ohio River) and, with some irony, in former states where slavery was legal or tolerated before the Civil War, including Missouri, Kansas, Oklahoma, and parts of Texas, Arkansas, Tennessee, and Kentucky, though most of these cities and states are not truly Midwestern. Parts of Colorado and Utah were settled by Midwestern migrants, and retain some "Heartland feeling", and because of trade ties, the province of Ontario has some cultural affinity to the Midwest. Generally, though, the region is bounded by the Ohio River, through the Great Plains to the Rockies and Canada.

The term West was applied to the region in the early years of the country. During this time, the vast majority of the population lived east of the Appalachian Mountains, but the country's borders stretched west all the way to the Rocky Mountains. Later, the vast region west of the Appalachians was divided into the Far West (now just the West), and the Middle West. Some parts of the Midwest have also been referred to as North West for historical reasons (for instance, this explains the Minnesota-based Northwest Airlines and the former Norwest Bank), so the current Northwest region of the country is called the Pacific Northwest to make a clear distinction.

The Midwest term is used sometimes interchangeably with the Heartland term to refer to "Middle America" and its citizens, "Middle Americans". Heartland states would seem to increasingly include states like Arkansas and Oklahoma, whom Atlanta-based CNN referred as the location of the "tragedy in the Heartland". Because the middle of the country has sometimes lagged the Coasts and Sunbelt states in agriculture and industry, the poverty of Southern border states and the religious character there leads some to include these states, like Kentucky, West Virginia, Tennessee, and Arkansas in a definition of the "Heartland".