The forests of the Ozarks and Appalachians have undergone considerable change over time. The landscape 12,000 years ago, as the Pleistocene Epoch came to a close, was more similar to the forests that currently exist at high latitudes today than those currently found in the two regions. Native Americans first arrived more than 14,000 years ago, when elements of the Pleistocene megafauna were not yet extinct. Although their numbers were low, artifacts left behind by these early Native Americans recovered from at a number of sites in the Appalachians and Ozarks date back to 12,000–14,000 years ago. The impact of Native Americans on the landscape was likely very minimal until about 3000 years ago when what is known as the Woodland Period began. By that time, the forests of the two regions had essentially reached what was their modern (at least pre-European colonization) expression. The purpose of this chapter is to describe the history of the Appalachians and Ozarks over the past 20,000 years, with a particular focus on the human inhabitants of the two regions.