The volume of continental groundwater is enormous, rivalling the amount found in ice sheets. Fluxes from groundwater to surface water are responsible for generating a substantial portion of streamflow globally but these fluxes are dominated by relatively shallow groundwaters (<500 m deep) and have short residence times. Deeper groundwaters are responsible for generating only a small amount of streamflow and a disproportionate amount of depletion of storage relative to streamflow capture tends to occur when they are pumped. The relative isolation of deeper groundwater systems has made these environments a target for carbon sequestration, disposal of produced waters from the oil and gas industry and nuclear waste isolation. However, despite the small fluxes of water between deep groundwater and the rest of the hydrologic cycle, geochemical fluxes can be substantial due to the elevated concentrations of many elements in deep groundwater. Deep groundwaters also contain microbial ecosystems that make up a considerable amount of the Earth’s biomass. Studying these systems is challenging not only due to the fewer windows into deeper subsurface but also because of the different processes and time scales that should be considered. While topography-driven flow still dominates many deep groundwater systems, variations in fluid density and various geological processes can drive fluid flow. Boundary conditions need to consider shifts in climate and geologic forcings over long time periods and, in some cases, changes in the flow system geometry, notably due to burial and denudation.  Improving our understanding of this frontier of hydrology will require new approaches, new tools and collaboration with other disciplines in the geosciences and beyond.