Land use and climate change can accelerate the depletion of freshwater resources that support humans and ecosystem services on a global scale. Here, we briefly review studies from around the world, and highlight those in this special issue. We identify stages that characterize increasing interaction between land use and climate change. During the first stage, hydrologic modifications and the built environment amplify overland flow via processes associated with runoff-dominated ecosystems (e.g., soil compaction, impervious surface cover, drainage, and channelization). During the second stage, changes in water storage impact the capacity of ecosystems to buffer extremes in water quantity and quality (e.g., either losses in snowpack, wetlands, and groundwater recharge or gains in water and nutrient storage behind dams in reservoirs). During the third stage, extremes in water quantity and quality contribute to losses in ecosystem services and water security (e.g., clean drinking water, flood mitigation, and habitat availability). During the final stage, management and restoration strategies attempt to regain lost ecosystem structure, function, and services but need to adapt to climate change. By anticipating the increasing interaction between land use and climate change, intervention points can be identified, and management strategies can be adjusted to improve outcomes for realistic expectations. Overall, global water security cannot be adequately restored without considering an increasing interaction between land use and climate change across progressive stages and our ever-increasing human domination of the water cycle from degradation to ecosystem restoration.