The investigation of dynamic fully integrated cultural-environmental systems is one grand challenge facing archaeologists in this century. In the Midwest and Southeast United States, archaeologists recently increased their study of Mississippian social systems (ca. AD 1000–1600) in relationship to paleoclimate and paleoenvironmental data. Significant differences in chronological control between archaeological chronologies and paleoenvironmental records pose challenges to the study of cultural-environmental systems in this region and often result in equifinal results. Three major lines of paleoenvironmental records are reviewed: bald cypress tree-ring records, the Living Blended Drought Atlas (LBDA), and lake-bottom sediment cores. The strongest approaches include local and regional multiproxy environmental records from the same location as a well-investigated archaeological site(s) or region(s). In the rare case where the cores also encode a regional population history, it may be possible to develop stronger inferences that consider variation within and between communities and their vulnerability to climate change and environmental catastrophes.