Caprocks are impermeable sedimentary formations that confine fluids, such as CO2 or H2, in storage formations. Caprocks are typically shale and they provide a barrier to vertical migration of buoyant fluids. While shale formations are ubiquitous throughout the subsurface, our fundamental and engineering science knowledge of them is limited by their nanoporous structure and extreme heterogeneity that spans at least 10 orders of magnitude spatially. This presentation is arranged around four challenges to enable system-level understanding of caprock seals: (1) the physics of fluid transport that makes seals effective barriers; (2) the reactive and mechanical behavior of caprock seals (3) reactivity of solid/fluid interfaces governed by complex processes that are strongly coupled to transport and mechanics; and (4) the relationship among rock fabric and the description of physicochemical processes at any single scale of observation. We highlight that some caprock/fluid systems undergo a self-sealing process due to coupled geochemical and geomechanical phenomena.