Human activities exert global-scale impacts on our environment with significant implications for freshwater-driven services and hazards for humans and nature. Our approach to the science of hydrology needs to significantly change so that we can understand and predict these implications. Such an adjustment is a necessary prerequisite for the development of sustainable water resource management strategies and to achieve long-term water security for people and the environment. Hydrology requires a paradigm shift in which predictions of system behavior that are beyond the range of previously observed variability or that result from significant alterations of physical (structural) system characteristics become the new norm. To achieve this shift, hydrologists must become both synthesists, observing and analyzing the system as a holistic entity, and analysts, understanding the functioning of individual system components, while operating firmly within a well-designed hypothesis testing framework. Cross-disciplinary integration must become a primary characteristic of hydrologic research, catalyzing new research and nurturing new educational models. The test of our quantitative understanding across atmosphere, hydrosphere, lithosphere, biosphere, and anthroposphere will necessarily lie in new approaches to benchmark our ability to predict the regional hydrologic and connected implications of environmental change. To address these challenges and to serve as a catalyst to bring about the necessary changes to hydrologic science, we call for a long-term initiative to address the regional implications of environmental change.