High overpressures are present within low permeability mudstones where there have been multiple, very large, submarine landslides during the Pleistocene. IODP Expedition 308 used weighted-mud to drill, core, and take direct pressure measurements in this challenging environment. Overpressures measured during Integrated Ocean Drilling Program (IODP) Expedition 308 reach 70% and 60% of the hydrostatic effective stress in the first 200 meters below sea floor (mbsf) at Sites U1322 and U1324, respectively, in the deepwater Gulf of Mexico, offshore Louisiana. Submarine landslides are recorded by a nearly transparent seismic facies that correlates to pronounced increases in bulk density, shear strength, and resistivity, relative to bounding undeformed sediment. This facies occurs as folded and homogenized mud, with rare mud clasts in cores. The average sedimentation rate from the seafloor to the top of the Blue Unit is 12 mm/year at Site U1324 and 3.6 mm/yr at Site U1322. Ursa mudstones have hydraulic diffusivities of 2 X 10 (super -8) m (super 2) /s whereas siltstones have diffusivities greater than 2 X 10 (super -7) m (super 2) /s. We interpret that during the Pleistocene, high overpressures were generated by rapid sedimentation of low permeability material from the ancestral Mississippi River. We present simulations that illustrate how high overpressure near the seafloor reduces slope stability and provides a mechanism for the large submarine landslides and low regional gradient (2 degrees) offshore from the Mississippi delta.