“Groundwater is a finite resource under continuous external pressures. Current unsustainable groundwater use threatens the resilience of aquifer systems and their ability to provide a long-term water source. Groundwater storage is considered to be a factor of groundwater resilience, although the extent to which resilience can be maintained has yet to be explored in depth. In this study, we assess the limit of groundwater resilience in the world’s largest groundwater systems with remote sensing observations. The Total Groundwater Stress (TGS) ratio, defined as the ratio of total storage to the groundwater depletion rate, is used to explore the timescales to depletion in the world’s largest aquifer systems and associated groundwater buffer capacity. We find that the current state of knowledge of large-scale groundwater storage has uncertainty ranges across orders of magnitude that severely limit the characterization of resilience in the study aquifers. Additionally, we show that groundwater availability, traditionally defined as recharge and re-defined in this study as total storage, can alter the systems that are considered to be stressed versus unstressed. We find that remote sensing observations from NASA’s Gravity Recovery and Climate Experiment can assist in providing such information at the scale of a whole aquifer. For example, we demonstrate that a groundwater depletion rate in the Northwest Sahara Aquifer System of 2.69 ± 0.8 km³ per year would result in the aquifer being depleted to 90% of its total storage in as few as 50 years given an initial storage estimate of 70 km³ [Swezey, 1999].”