Thomas Jefferson (1743-1826), the third President of the United States, faced many challenges, both personal and moral in nature. First, his beloved wife, Martha, died in 1782 at age 33 as a result of suffering from diabetes and bearing many children. Jefferson was in a long state of mourning following her death, and it is thought by many historians that he had a long relationship with Sally Hemings, a slave woman of biracial ancestry, after his wife died. Sally was the half-sister of his wife, Martha, and likely had six children with Jefferson.

Jefferson was also challenged morally by the issue of slavery. He had proposed releasing and retraining slaves, and he wanted to insert into the Declaration of Independence a statement criticizing King George III of England for his support of the slave trade (this section was taken out). However, as President, Jefferson allowed slavery into the territories acquired in the Louisiana Purchase, and he did not support emancipation while President. In addition, he only freed some of his slaves, and he was clearly divided about the issue of whether slaves could lead independent lives right after slavery, though he thought slaves had inalienable rights as human beings.

The election of 1800 that brought Jefferson to the presidency as a Democratic-Republican (then known as a Republican) was also a highly bitter and controversial one. Jefferson and Aaron Burr were tied in the electoral college, and the House of Representatives, which had to then decide the election, cast the deciding votes for Jefferson after several ballots and lobbying by Alexander Hamilton. Burr became Jefferson's Vice-President.

During Jefferson's presidency, he often carried out actions that were contrary to his stated beliefs. While he advocated a small federal government, he increased the complexity of the role of the federal government through the Louisiana Purchase in 1803. Members of his party were not sure whether the federal government had the right to acquire land, but Jefferson did so anyway.

Jefferson also faced international challenges. In his second term in the White House, Jefferson tried to avoid U.S. entanglement in the Napoleonic Wars. During these wars, the British and French were interrupting American shipping, so Jefferson declared an embargo on American shipping. However, this embargo is thought to have mainly hurt the U.S. After his second term, he retired to his house in Monticello.