Abstract In the eastern mid-continent United States, the Cambrian Mt. Simon Sandstone is a likely deep-saline reservoir target for CO 2 sequestration. The overlying Cambrian–Ordovician Knox carbonate section will be an important part of the confining interval for the Mt. Simon, as much of the Knox is dominated by dense (<0.01 md), well-cemented dolomites with little or no permeability. The Knox, however, does contain discrete zones of porosity and permeability and is locally an important oil and gas producer, as well as gas storage unit. The Knox needs to be considered in any sequestration project in the region because in some localities carbonate and sandstone zones within the unit have better reservoir characteristics than the underlying Mt. Simon or overlying St. Peter Sandstone. An example of such a locality is the DuPont waste-injection site at Louisville, Kentucky, where a thick Mt. Simon section was tested and then abandoned in favor of a fractured, vuggy dolomite facies in the overlying lower Knox with an injectivity rate as high as 568 liters per minute (150 gallons per minute). Thick, dense carbonates of the Knox enveloped the reservoir effectively sealing the porous and permeable zones within the same stratigraphic unit. This is not an exceptional circumstance because several deep tests of Cambrian–Ordovician clastics in the region have encountered tight sandstone in the target horizon but vuggy and fracture porosity in overlying Knox carbonates. Analyses of known Knox enhanced oil recovery operations, waste-injection wells, and gas storage fields illustrate that liquids and gases can be effectively and safely retained within Knox reservoirs. However, porous and permeable zones within the units that constitute the local reservoirs are discontinuous and heterogeneous, and data describing the detailed characteristics of these reservoirs are sparse. More deep subsurface data are needed to better characterize the Knox and similar carbonates in other regions for their use as potential carbon sequestration reservoirs. Some of these data are currently being collected through the U.S. Department of Energy’s Carbon Sequestration Regional Partnership programs.