Historically, the Brazos River spanned eight ecoregions on its 2,060 km journey from New Mexico, through the heart of Texas, to the Gulf of Mexico. This prairie stream ecosystem supports over 60 fish species including two endangered cyprinids. Sixteen major reservoirs control streamflow and create distinct, disconnected fragments. Long-term ecological studies have provided a strong science foundation for guiding water management and watershed conservation. Opportunities to restore and protect environmental flows include informing flow standards, negotiating flow and water level agreements, and identifying surface water permits and groundwater rights with high conservation value. Riparian management, including implementation of best management practices and control of invasive saltcedar in the upper Brazos watershed, not only seeks to improve habitat for fish and wildlife but also to improve base flows. Barriers (e.g., road-crossings, drying, and dams) hinder successful recruitment, migration, and recolonization of prairie fishes. Ongoing research seeks to identify stream reaches most threatened by drying where aquifer pumping may reduce groundwater inflows to streams, especially during dry times. Removal and mitigation of barriers, as appropriate, will be critical to restoring ecological functions and connectivity. Propagation and repatriation efforts are also underway to support native fish conservation and recovery in the Brazos River.