We assess the ability of global water systems, resolved at 282 assessment subregions (ASRs), to the meet water requirements under integrated projections of socioeconomic growth and climate change. We employ a water resource system (WRS) component embedded within the Massachusetts Institute of Technology Integrated Global System Model (IGSM) framework in a suite of simulations that consider a range of climate policies and regional hydroclimate changes out to 2050. For many developing nations, water demand increases due to population growth and economic activity have a much stronger effect on water stress than climate change. By 2050, economic growth and population change alone can lead to an additional 1.8 billion people living under at least moderate water stress, with 80% of these located in developing countries. Uncertain regional climate change can play a secondary role to either exacerbate or dampen the increase in water stress. The strongest climate impacts on water stress are observed in Africa, but strong impacts also occur over Europe, Southeast Asia, and North America. The combined effects of socioeconomic growth and uncertain climate change lead to a 1.0–1.3 billion increase of the world's 2050 projected population living with overly exploited water conditions—where total potential water requirements will consistently exceed surface water supply. This would imply that adaptive measures would be taken to meet these surface water shortfalls and include: water-use efficiency, reduced and/or redirected consumption, recurrent periods of water emergencies or curtailments, groundwater depletion, additional interbasin transfers, and overdraw from flow intended to maintain environmental requirements.