Above, a marker on a trail near Swannanoa Gap, a major pass over the Blue Ridge Escarpment used by animals and native peoples for thousands of years. This trail served as a connecting gap for the Catawba River settlements and the Middle Towns of the Cherokee Nation.

The Cherokee world was divided into clusters of towns that were separated by mountain ranges. The Overhill Towns were located on the Tennessee River just south of Knoxville. Across the Unaka Mountains to the east were the Valley Towns of the Valley and Hiwassee Rivers, near Murphy in western North Carolina. The Middle Towns lay along the Little Tennessee River north and south of the modern town of Franklin. Out Towns were located farther north and east along the Tuckasegee River in Swain and Jackson counties. The Lower Towns were located between Charles Town, South Carolina, and northern Georgia. An intricate trail network radiated out in every direction, connecting all the Cherokee towns and linking into a vast, continental Indian trail system.

In the mid-1700s, John Stuart listed fourteen Middle Towns, among which were Cowee and Nikwasi (also Nuqose, Nuquose) on the Little Tennessee River, north of present-day Franklin, North Carolina. The Middle Towns along the Little Tennessee River were destroyed by the English General Grant in 1761. Surviving Indians fled into the mountains and returned later to rebuild their homes. James Adair, in his History of the American Indians, wrote in 1775, "I have gathered good hops in the woods opposite Nuquose, where our troops were repelled by the Cheerakee in the year 1760. There is not a more healthful region under the sun, than this country; for the air is commonly open and clear, and plenty of wholesome and pleasant water...almost as transparent as glass."

As treaties and cessions allowed the white planters and traders to inch their way to the escarpment of the Appalachians and Blue Ridge, Native Americans realized this mountain range was a natural boundary the white man must not pass. On the other side were Tennessee and Kentucky.

For a time, the Appalachian Mountains were an insurmountable obstacle to white expansion. But "hide hunters" like Daniel Boone and others coveted the buffalo and other game that abounded in the "Kaintucke" wilderness and the discovery of the Indian passage across the Cumberland Gap changed the course of history in British expansion in the Appalachians. In 1775, while in the employment of a land speculation company known as the Transylvania Company, Boone traveled from Fort Chiswell in Virginia, through the Cumberland Gap and into central Kentucky, often following Indian trails. The team of 35 loggers he led widened the trail through the Cumberland Gap, near the borders of Tennessee, Kentucky, and Virginia. This became known as the Wilderness Road. From the Cumberland Gap to Flat Lick, Kentucky, Boone's Trace followed a well established Indian trail. In the 1790s, the Wilderness Road was widened again to accommodate wagons. As a result, an estimated 200,000 to 300,000 white settlers poured through the Cumberland Gap before 1810.

Another principal artery was the Great Warpath, which connected the Gulf of Mexico with the Great Lakes. It skirted the Great Smoky Mountains on the western flank. Later, sections of it became the Federal Road in Tennessee. Ted Franklin Belue, noted in The Long Hunt, "Alabama Creeks hunkered along its banks to attack the Overhill Cherokees who lived in the Blue Ridge. The war road led to Long Island, in east Tennessee, then forked. One prong went past the Holston Valley to what is now Saltville, Virginia; the other cut into Pennsylvania." As with other war roads, some of the trees along the Great Warpath were marked with blazes, and with arborglyphs smeared with red paint.