Long term containment of stored CO2 in deep geological reservoirs will depend on the performance of the caprock to prevent the buoyant CO2 from escaping to shallow drinking water aquifers or the ground surface. Here we report new laboratory experiments on CO2–brine–caprock interactions and a review of the relevant literature. The Eau Claire Formation is the caprock overlying the Mount Simon sandstone formation, one of the target geological CO2 storage reservoirs in the Midwest USA region. Batch experiments of Eau Claire shale dissolution in brine were conducted at 200 ◦C and 300 bars to test the extent of fluid-rock reactions. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) analysis indicate minor dissolution of K-feldspar and anhydrite, and precipitation of pore-filling and pore-bridging illite and/or smectite, and siderite in the vicinity of pyrite. We also reviewed relevant reactivity experiments, modeling work, and field observations in the literature in an attempt to help define the framework for future studies on the geochemical systems of the caprock overlain on geological CO2 storage formations. Reactivity of the caprock is generally shown to be low and limited to the vicinity of the CO2–caprock interface, and is related to the original caprock mineralogical and petrophysical properties. Stable isotope studies indicate that CO2 exists in both free phase and dissolved phase within the caprock. Carbonate and feldspar dissolution is reported in most studies, along with clay and secondary carbonate precipitation. Currently, research is mainly focused on the micro-fracture scale geochemistry of the shaly caprock. More attention is required on the potential pore scale reactions that may become significant given the long time scale associated with geological carbon storage.