New Zealand's Waikato River has had a short but intense history of development, primarily through land-use change and flow regulation in the upper river, and in the lower river through flood control works, non-native species invasion, and land-use intensification. The river undergoes sharp transitions across montane-flood plain-coastal environments over a short distance and under similar climate. Together with specialized life-history requirements of many native fish, these features provide valuable insights into large river ecology and management. Testing approaches to determine outcomes of water quality changes have highlighted the value of functional indicators over traditional biotic measures for monitoring anthropogenic impacts. Initiatives to enhance native fish populations in the lower river have included remediation of migration barriers to improve access to tributary habitat, enhancement of tidal spawning habitat, and traps and gates to limit movement of large pest fish into flood plain lakes for spawning. This example of a southern temperate large river system highlights the importance of recruitment habitat and connectivity for native fish communities dominated by migratory species. Their slender bodies provide opportunities to create semipermeable barriers that enable access to flood plain habitats while restricting larger invasive fish. Recent initiatives have increased momentum to restore the ecological health of this river, but the underpinning science to guide priority actions is often lacking, and there is limited monitoring over the scales and time frames required to evaluate effectiveness.