One such rift was the rift between Jefferson and Burr. Burr, whose political ambition was considered dangerous by both Democratic-Republicans and Federalists, was dropped as Jefferson's running mate in 1804 and replaced by George Clinton. Burr would later go on to kill Alexander Hamilton in a duel, killing his own political career in the process. Later, Burr would go on to try to establish his own country in the West with the aid of American soldiers of fortune.

Jefferson also opened secret negotiations with France to buy Florida in 1805. While many Democratic-Republicans were ardent expansionists, the move was considered controversial as some in the party believed that Jefferson was overstepping his bounds as Chief Executive. While Jefferson was largely cheered by his own party and hated by Federalists, his tendency to act without paying heed to other interest groups alienated many. His Embargo Act hurt Federalists in the Northeast and hit the cotton industry in the South. Jefferson's decrease of military involvement also lost him the support of many Democratic-Republican military officers. The officers saw the potential upcoming wars with France and Britain as being disastrous for the young country. Jefferson's selection of James Madison as a successor helped to make the Democratic party more regional. Some complained that it seemed as though Virginia had a virtual monopoly on the presidency.