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The George Thompson papers contain letters and documents primarily concerning Kentucky politics and conflicts between Native Americans and white settlers at the close of the 18th-century and during the war of 1812.

The George Thompson papers contain 32 items (29 letters and 3 documents) spanning 1784-1831. The materials relate to George Claiborne Thompson, who served as a Virginia colonel in the Revolutionary War and a surveyor and politician thereafter, and his son, George Claiborne Thompson, Jr. Isaac Shelby, the governor of Kentucky, wrote the first 4 letters in the collection between 1784 and 1788 to the senior Thompson. The first three contain details related to the surveying of land in present-day Kentucky, including information on geographical features, the expense of making surveys, and land claims. In the fourth letter, dated November 14, 1788, Shelby described a case of an African American man who was brought from Maryland to the "District of Kentucky" and had applied for his freedom under the Acts of Assembly of 1778 and 1785. Shelby noted that the case might "open the way to every negroe in the District to take the same steps."

A substantial number of letters in the collection concern Native Americans, particularly their ongoing clashes with white settlers. On June 1, 1790, George Thompson wrote to James Madison, describing a three-hour battle on the Ohio River between his party and 61 "Indians," who took two boats and other property. He also reported several other incidents, including the killing of John May by natives and the scalping of three white children in the area. Other correspondents reported on engagements with Native Americans in the War of 1812. On February 20, 1813, Isaac Shelby related an account by Frenchman Adelard Labbedie of the Battle of River Raisin, including the surrender of General Winchester and the killing of wounded American prisoners by "about 10 Indians."

The George Thompson papers also shed light on American and Kentucky politics in the late-18th and early-19th centuries. They include U.S. Senator John Breckinridge's discussion of the Louisiana Purchase and the surrender of New Orleans (November 4, 1803), Isaac Shelby's rationale for not running for Congress (April 23, 1803), and several reports on the Kentucky legislature by George Thompson, Jr. On October 16, 1821, he wrote to his father informing him that he, Thompson, Jr., had been named speaker of the Kentucky House of Representatives for the new term. The collection closes with several undated legal documents stemming from lawsuits over Kentucky land between George Thompson, Sr., and several other men.