Isolation of spent nuclear fuel assemblies in deep vertical boreholes is analyzed. The main safety features of the borehole concept are related to the repository’s great depth, implying (a) long migration distances and correspondingly long travel times, allowing radionuclides to decay, (b) separation of the repository from the dynamic hydrological cycle near the land surface, (c) stable geological and hydrogeological conditions, and (d) a geochemically reducing environment. An integrated simulation model of the engineered and natural barrier systems has been developed to examine multiple scenarios of the release of radionuclides from the waste canisters, the transport through a fractured porous host rock, and the extraction of potentially contaminated drinking water from an aquifer. These generic simulations include thermal effects from both the natural geothermal gradient and the heat-generating waste, the influence of topography on regional groundwater flow, moderated by salinity stratification at depth, and the role of borehole sealing. The impact of these processes on the transport of select radionuclides is studied, which include long-lived, soluble, sorbing or highly mobile isotopes along with a decay chain of safety-relevant actinide metals. The generic analyses suggest that a deep vertical borehole repository has the potential to be a safe option for the disposal of certain waste streams, with the depth itself and the stable hydrogeological environment encountered in the emplacement zone providing inherent long-term isolation, which allows for reduced reliance on a complex engineered barrier system.