Climate change will increase water stress in many regions placing greater pressures on rivers to meet human and ecological water needs. Managing rivers experiencing water stress requires a fundamental understanding of how ecosystem processes and functions respond to natural and anthropogenic drivers of flow variability and change. The field of environmental flows meets this need by defining “flow-ecology” relationships—mathematical models linking ecological characteristics and dynamics to the underlying flow regime. However, because these relationships are most often based on historical hydrologic regimes, they implicitly assume climatic stationarity. A fundamental challenge in the Anthropocene is how to model flow-ecology relationships such that the effects of nonstationarity can be captured. In the present article, we introduce a novel approach that addresses these shortcomings and show its utility through a series of conceptual and empirical examples. The framework incorporates ecological dynamics and uncertain future hydrologic conditions, as well as nonstationarity itself, thereby providing a viable framework for modeling flow-ecology responses to inform water management in a rapidly changing climate.