Population growth, economic development, and dietary changes have drastically increased the demand for food and water. The resulting expansion of irrigated agriculture into semi-arid areas with limited precipitation and surface water has greatly increased the dependence of irrigated crops on groundwater withdrawal. Also, the increasing number of people living in mega-cities without access to clean surface water or piped drinking water has drastically increased urban groundwater use. The result of these trends has been the steady increase of the use of non-renewable groundwater resources and associated high rates of aquifer depletion around the globe. We present a comprehensive review of the state-ofthe-art in research on non-renewable groundwater use and groundwater depletion. We start with a section defining the concepts of non-renewable groundwater, fossil groundwater and groundwater depletion and place these concepts in a hydrogeological perspective. We pay particular attention to the interaction between groundwater withdrawal, recharge and surface water which is critical to understanding sustainable groundwater withdrawal. We provide an overview of methods that have been used to estimate groundwater depletion, followed by an extensive review of global and regional depletion estimates, the adverse impacts of groundwater depletion and the hydroeconomics of groundwater use. We end this review with an outlook for future research based on main research gaps and challenges identified. This review shows that both the estimates of current depletion rates and the future availability of non-renewable groundwater are highly uncertain and that considerable data and research challenges need to be overcome if we hope to reduce this uncertainty in the near future.