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In the winter of 1811-12, three powerful earthquakes struck the Mississippi River Valley. The two largest were about 50 times more powerful than the recent Kobe, Japan shock (>5000 dead, ~$200 billion damage). According to current scientific understanding, these were 'earthquakes where they shouldn't be. They are the outstanding examples of the rare major-to-great earthquakes that happen remote from the usual tectonic plate boundary or active intraplate seismic zones. Our understanding of the faulting process and repeat times of New Madrid characteristic earthquakes has greatly improved recently but major questions remain. Advances toward answering these questions have required interdisciplinary studies, integrating seismology, historical research, statistics, archaeology, geophysics, geotechnical engineering and tectonic geomorphology. In the nineteenth century New Madrid released more seismic energy than the western U.S., including the San Andreas Fault. In the twentieth century the fault zone has been relatively quiescent with only a few, minor-damage events exceeding magnitude 5. Understanding which century is more representative of "normal" New Madrid behavior is perhaps our greatest current challenge.