Engineered projects resulting in unintended consequences, coastal erosion, subsidence, and sea-level rise are rapidly destroying archaeological sites in the Mississippi River Delta (MRD). The processes of site obliteration are intensifying and accelerating due to anthropogenic transformation of the environment, including cumulative engineered alterations of the landscape and climate change. Combined with increased inundation and erosion from storm surges, hundreds of terrestrial sites formerly located on natural levees, barrier islands, and other coastal landforms are progressively eroded, redeposited, deeply buried, and submerged. These include thousand-year-old earthen mounds and shell middens constructed by Native Americans, as well as centuries-old fishing communities along the coast. These irreplaceable cultural properties can provide crucial information on the unique history and ecology of the MRD. Ongoing studies include consulting with interested parties and implementing data sharing agreements. Re- searchers have formed a consortium of universities and state and federal agencies, and are partnering with culturally affiliated Native American tribes, descendant groups, and coastal communities. The consortium is developing a robust GIS-enabled risk matrix for analyzing threats and effects to endangered sites. It is using the risk matrix to select 30 sites for monitoring, assessment, aerial photogrammetry, and recording environmental data on water table fluctuations. Analysis of action-based scientific data on these imperiled and rapidly disappearing places is urgently needed and will provide the impetus and baseline for future studies. Otherwise, ongoing site destruction will erase any remaining opportunities for learning about Louisiana’s deep history and diverse cultural heritage.