Understanding the effects of hydrology on fish populations is essential to managing for native fish conservation. However, despite decades of research illustrating streamflow influences on fish habitat, reproduction, and survival, biologists remain challenged when tasked with predicting how fish populations will respond to changes in flow regimes. This uncertainty stems from insufficient understanding of the context-dependent mechanisms underlying fish responses to, for example, periods of reduced flow or altered frequency of high-flow events. We aim to address this gap by drawing on previous research to hypothesize mechanisms by which low and high flows influence fish populations and communities, identifying challenges that stem from data limitations and ecological complexity, and outlining research directions that can advance an empirical basis for prediction. Focusing flow ecology research on testing and refining mechanistic hypotheses can help narrow management uncertainties and better support species conservation in changing flow regimes.