Climate change and a host of other human stressors on aquatic systems in the American Southwest are rapidly exceeding our ability to conserve native fish diversity. The most severe megadrought in over a millennium has compromised current management plans by exacerbating the impacts of altered hydrology, poor water quality, invasive species, and habitat 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 draw examples from current literature and empirical research to support our contention that more resources and novel approaches to prioritizing environmental flows, improving ecological connectivity of populations, preventing and controlling invasive species, and establishing refuge populations are necessary to stave off extinctions. Moreover, shifts in socio-political attitudes that better recognize environmental concerns must be integrated into water resource policy and management to achieve native fish conservation goals.