Many aquatic ecosystems have been severely degraded by water-resource development affecting flow regimes and biological connectivity. Freshwater fish have been particularly affected by these changes and climate change will place further stress on them. The Murray-Darling Basin (MDB), Australia, represents a highly affected aquatic system with dramatically modified flow regimes. This has impaired the health of its rivers, and potentially limited the adaptive capacity of its biota to respond to a changing climate. Here, we present our predictions of the potential impacts of climate change on 18 native fish species across their distributional ranges against the back-drop of past and continuing water-resource development (WRD). Because most of these species are found across a wide range of geographical and hydrological settings, we classified the MDB into 10 regions to account for likely variation in climate-change effects, on the basis of latitude, elevation and WRD. Cold water-tolerant species will be under greater stress than are warm water-tolerant species. In some regions, the negative impacts on exotic fish such as trout are likely to improve current conditions for native species. Because the impacts of climate change on any given species are likely to vary from region to region, regional fish assemblages will also be differentially affected. The most affected region is likely to occur in the highly disturbed Lower Murray River region, whereas the dryland rivers that are less affected in the northern MDB are likely to remain largely unchanged. Although climate change is a current and future threat to the MDB fish fauna, the continued over-regulation of water resources will place as much, if not more, stress on the remnant fish species.