The Murray-Darling Basin (MDB) is a highly allocated and regulated, mostly semiarid basin in south-eastern Australia, where groundwater is a significant water resource. Future climate predictions for the MDB include an expansion of arid and semiarid climate zones to replace temperate areas. The impacts of climate change are already evident in declining groundwater levels and changes in the connection status between rivers and groundwater, and modelling has predicted a further reduction in future groundwater recharge and ongoing declines in groundwater levels. This is predicted to further reduce river baseflow and negatively impact groundwater-dependent ecosystems (GDEs), and these system responses to a changing climate and extreme events are complex and not always well understood. This report provides an overview of the current state of knowledge of groundwater response to a changing climate for the MDB, and outlines challenges and opportunities for future groundwater research and management. Opportunities for the region include improving data systems and acquisition through automation and novel data sources, and growing capability in integrated, risk-based modelling. Quantification of the groundwater/surface-water connection response to declining groundwater levels, and assessing GDE water requirements and thresholds, would enable identification of vulnerable systems and inform the development of metrics for adaptive management, improving the ability to respond to climate extremes. There is potential to adapt policy to support active management of groundwater where required, including conjunctive use and water banking. Improving knowledge sharing and water literacy, including understanding community values of groundwater and GDEs, would support future decision-making.