Climate change is likely to cause deleterious hydrological and ecological impacts in many of the world’s major river basins. Using the Murray-Darling Basin, Australia, as a case study, we present an adaptation framework which addresses the hydrological impacts of climate change at three spatial scales: the high-conservation value asset, the water management unit and the entire basin. At each scale, the appropriate scientific, policy and operational tools differ, though should be applied in concert. At the scale of the asset, hydrodynamic modelling has improved the capacity of site managers to anticipate the effects of management interventions. These models have also contributed to improve hydrological modelling of the water management unit. When combined with ecosystem response models, hydrological models can compare ecological outcomes over a range of timescales, leading to improvements in the representation of environmental requirements in water sharing plans. At the scale of the basin, the Australian government has used a legislative mechanism to set overarching ecological and diversion objectives. In addition, the purchase of water-use entitlements has created a flexible mechanism to use the water market as a climate-change adaptation mechanism, responding to the changing water availability and conservation priorities that emerge over the coming decades.