This research examines the human-environment interactions on St. Catherines Island, Georgia, during the late Woodland through the Mississippian period (AD 8001580). Results from multiple analyses indicate that socio-political, demographic, and economic changes during this period were associated with changes in subsistence, settlement, and land-use patterns. Archaeofaunal collections of vertebrates and invertebrates are examined from three sites in a single locality, representing human occupation during the entire Mississippian period9LI21, 9LI229, and 9LI230. Two additional late Mississippian archaeofaunal collections of vertebrates are examined from different island locations9LI207 and 9LI1637. Fine-grained recovery techniques, not previously used for Mississippian deposits on St. Catherines Island, produced collections dominated by estuarine resources, especially oysters, clams, stout tagelus, sea catfishes, mullets, killifishes, and drums. Previous methods used to recover faunal remains produced collections dominated by deer. This study suggests that, though deer contributed large amounts of meat to the diet, estuarine resources were more abundant and contributed the most meat. A Mississippian chiefdom developed on the island during the Irene phase (AD 13001580), with social inequality, large and dense populations living in communities of multiple, integrated settlements, and maize farming. Zooarchaeological evidence presented in this study suggests these socio-political changes led to new human-environment interactions, compared to the early Mississippian period. Irene peoples used a larger number and wider variety of shellfishing and fishing locations than early Mississippian folk. The Irene fishing strategy caught more large fishes and may have involved a shift to larger-scale mass-capture techniques, such as weirs. Irene settlements were occupied for longer periods of time and waste disposal was more organized than in earlier periods. These land-use and subsistence changes affected animal populations. Increased exploitation of estuarine resources influenced growth rates of clams and catfishes. Over time, the landscape became more open and heterogeneous, affecting the foraging habits of deer. These subtle changes are observed because of the fine-grained recovery and multiple analyses of multiple taxa. Yet, overall, the St. Catherines Island subsistence-settlement strategy, focusing on a specific suite of estuarine resources, supplemented with the occasional deer, was stable for thousands of years.