Water issues are rarely simple. At the global scale, water is at the focus of a powerful multifaceted challenge. Demands for both consumptive and nonconsumptive uses are growing, while climate change is at the same time decreasing availability in some places and increasing risks of heavy precipitation in many others. Through diverse mechanisms that interact with natural processes, human activities impact not only the quantity of water available but also its quality. Here we explore the multiway interactions among water, climate, energy, and food through a number of case studies illustrating the interconnected web of competing drivers, demands, and trade-offs that frame humanity's decisions about water use. The net result of this complex mix of drivers and processes is that water issues need to be addressed with a systems perspective. While a systems framing can be daunting, integrated approaches are fundamental to identifying and evaluating options for sustainable solutions.