Climate change and human impacts on aquatic systems in the American Southwest are rapidly exceeding our ability to conserve native fishes. The most severe megadrought in over a millennium has exacerbated and complicated conservation challenges including altered hydrology, poor water quality, invasive species, and fragmentation. Drought legacies are of particular concern, and existing conservation actions may not be sufficient to maintain resilient native fish populations, particularly if this drought persists. We contend that more resources and novel approaches to prioritizing environmental flows, improving connectivity of populations, controlling invasive species, and establishing refuge populations are necessary to stave off extinctions. Moreover, shifts in socio-political attitudes that better recognize environmental concerns need to be integrated into water resource policy and management to achieve native fish conservation goals.