Deep, saline, water-bearing reservoirs offer the greatest potential for geological sequestration of large volumes of CO2. In the Midwestern United States, the deepest most significant saline reservoir is the Cambrian Mt. Simon Sandstone. The Mt. Simon Sandstone is commonly used for natural gas storage in relatively shallow parts of the Illinois Basin. By analogy, the data from these storage projects indicate that the unit is a heterogeneous reservoir with a large potential sequestration capacity. The Mt. Simon Sandstone consists of fine to coarse sandstone with some interbeds of gray shale. Laterally discontinuous shale and siltstone interbeds in the Mt. Simon Sandstone may serve as baffles to disrupt the vertical migration of the buoyant CO2. Fluid-flow modeling of CO2 injection into the Mt. Simon reservoir suggests that inferred discontinuous flow barriers actually increase the potential storage capacity by increasing the volume of the contacted reservoir. Fluid-flow modeling of the Manlove gas storage field in Champaign County, Illinois, depicts a buildup of CO2 saturation followed by lateral migration of CO2 to a vertical pathway that connects the intrareservoir units. Vertical migration then continues upward until the migrating CO2 is sealed beneath another impermeable or low-permeability shale interbed. The Eau Claire Formation, which directly overlies the Mt. Simon Sandstone, provides the primary seal that may ultimately prevent CO2 migration into shallower formations. The Mt. Simon Sandstone underlies most of Illinois, Michigan, Iowa, Indiana, and Ohio and has a maximum gross thickness greater than 790 m (2600 ft). However, the Mt. Simon Sandstone is relatively thin or absent above some localized basement paleotopographic high areas because of either nondeposition or erosion. These paleotopographic high areas are inferred from geophysical logs and two-dimensional and three-dimensional seismic reflection data. In addition to changes on the Precambrian surface caused by paleotopography, exploratory drilling for potential Mt. Simon CO2 storage reservoirs must contend with the combination of variations in paleotopography and reservoir pinch-outs as well as variations in structural closure. The Mt. Simon Sandstone underlies one of the largest concentrations of coal-fired power plants in the world and is therefore one of the most significant potential carbon storage resources in the United States. The Mt. Simon Sandstone has a potential sequestration capacity of between 27 and 109 billion metric tonnes of CO2. However, the potential for the Mt. Simon Sandstone as an effective reservoir for geological sequestration cannot be realized without an understanding of its complex internal stratigraphy and the relationship of structural configuration to paleotopography.