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The Louisiana Purchase of 1803 intensified American migration to the west that was already well underway. Anglo-American settlement in the 18th century had largely been confined to the eastern seaboard. It made its boldest inroads where rivers allowed easy internal transportation. As a result the chief population centers of early North America were clustered on the coast or along its major inland waterways.

In May 1804, a group of 50 Americans led by Meriwether Lewis, Jefferson's personal secretary, and William Clark, an army officer, headed northwest along the Missouri River from St. Louis. Their varied instructions reveal the multiple goals that Jefferson hoped the expedition could accomplish. While trying to find a route across the continent, they were also expected to make detailed observations of the natural resources and geography of the west. Furthermore, they were to establish good relations with native groups in an attempt to disrupt British dominance of the lucrative Indian fur trade of the continental interior.

While western movement and policies were reshaping the republic, European wars also presented a major challenge to the new country. The Napoleonic Wars (1802-1815) were a continuation of the conflict begun in the 1790s when Great Britain lead a coalition of European powers against Revolutionary France, though France was now led by the brilliant military strategist Napoleon Bonaparte. As had also been true in the 1790s, neither European superpower respected the neutrality of the United States. Instead, both tried to prevent U.S. ships from carrying goods to their enemy. Both Britain and France imposed blockades to limit American merchants, though the dominant British navy was clearly more successful.

In the 16th, 17th, and 18th centuries, the first white settlers in America inhabited the eastern seaboard. There the whites either made treaties with the Native American groups to buy land or they forcibly took Indian land. By the Revolution's end and on into the early 19th century, Native Americans were being displaced across the Appalachians and toward what is today the Midwest. For these exiled groups, there were few places left to go.

In the War of 1812 the United States once again fought against the British and their Indian allies. Some historians see the conflict as a Second War for American Independence.

The War of 1812 came to an end largely because the British public had grown tired of the sacrifice and expense of their twenty-year war against France. Now that Napoleon was all but finally defeated, the minor war against the United States in North America lost popular support. Negotiations began in August 1814 and on Christmas Eve the Treaty of Ghent was signed in Belgium. The treaty called for the mutual restoration of territory based on pre-war boundaries and with the European war now over, the issue of American neutrality had no significance.

The United States changed dramatically in its first half century. In 1776 the U.S. consisted of thirteen colonies clustered together on the eastern seaboard. By 1821 eleven new states had been added from Maine to Louisiana. This geographic growth and especially the political incorporation of the new states demonstrated that the United States had resolved a fundamental question about how to expand. This growth not only built upon the Louisiana Purchase, but included military intervention in Spanish Florida which the United States then claimed by treaty in 1819.

The transition from an agricultural to an industrial economy took more than a century in the United States, but that long development entered its first phase from the 1790s through the 1830s. The Industrial Revolution had begun in Britain during the mid-18th century, but the American colonies lagged far behind the mother country in part because the abundance of land and scarcity of labor in the New World reduced interest in expensive investments in machine production. Nevertheless, with the shift from hand-made to machine-made products a new era of human experience began where increased productivity created a much higher standard of living than had ever been known in the pre-industrial world.

The American Industrial Revolution, concentrated in the northeast, would ultimately prove to be the most significant force in the development of the modern United States. This economic innovation sprung primarily from necessity. New England's agricultural economy was the poorest in the country and that helped to spur experimentation there. Meanwhile, the far more fertile southern states remained fully committed to agriculture as the central source of its wealth, here, too, dramatic changes created a wholly new economy that would have been unrecognizable to late-18th century Americans.