As regional chronologies become better defined, we are better able to track large-scale population movements and related cultural change. A dataset of 156 radiocarbon dates from the Middle Cumberland Region (MCR), evaluated with 199 more dates from the Ridge and Valley portions of northern Georgia and East Tennessee, enable modeling of population movements from the Central Mississippi Valley into the MCR, as well as subsequent movements and effects in the Ridge and Valley between AD 1200 and 1450. The dissolution of Cahokia is of particular interest, because the MCR falls geographically between the American Bottom and the Ridge and Valley province. This large-scale chronological perspective places key events in this part of the Southeast and Midwest into a unified historical framework that increases our understanding of the timing of cultural events. A related goal is to sort out possible external events and influences that may have affected this large region. This study makes apparent the relationships between cultural events and natural events, such as the drought sequences reported for the Central Mississippi Valley and beyond.