The Burr Conspiracy, possibly a secessionist scheme, brought the nation's attention to the Western Virginia frontier early in the 19th century. The episode was fueled by Ohio Valley settlers' anger at being denied navigational access to the Mississippi River and by the frustrations of an ambitious politician. Col. Aaron Burr, vice president (1801—05) of the United States, had killed Alexander Hamilton in a duel in 1804 and fallen into disgrace. In 1805, Burr attempted to resuscitate his career by parlaying western sectional discontent into a military expedition into the Southwest. He traveled through the Ohio and Mississippi valleys to formulate his plans. During the trip, he met Harman Blennerhassett, a wealthy Irish expatriate living on an Ohio River island near present Parkersburg. Blennerhassett became one of Burr's financial backers and allowed his estate to serve as a base of operation.

Burr's plans unraveled in 1807 with his arrest while leading followers down the Mississippi. Despite the fact that his subsequent treason trial ended in acquittal, historians have remained divided as to the conspiracy's objectives. Was it a treasonous attempt to separate the West from the United States, a private military expedition against the Spanish-ruled Southwest, or, as Burr's defenders claimed, a peaceable attempt to settle western lands? The truth, obscured by the destruction of Burr's papers, probably will never be known.

The Burr conspiracy's enduring legal legacy was its clarification of the definition of treason in American law. President Jefferson, perhaps partly motivated by personal animosity, relentlessly prosecuted Burr. Chief Justice John Marshall's ruling in the Fourth Circuit federal court case, U.S. v. Burr, found that treason required overt action, rather than mere intention or even conspiracy, and that Burr had not crossed that line. The impact on the Blennerhassetts was ruinous, forcing them to flee their island home and ending a romantic episode of Ohio Valley history.