We review the human actions, proximal stressors and ecological responses for floodplain forests Australia’s largest river system—the Murray-Darling Basin. A conceptual model for the floodplain forests was built from extensive published information and some unpublished results for the system, which should provide a basis for understanding, studying and managing the ecology of floodplains that face similar environmental stresses. Since European settlement, lowlands areas of the basin have been extensively cleared for agriculture and remnant forests heavily harvested for timber. The most significant human intervention is modification of river flows, and the reduction in frequency, duration and timing of flooding, which are compounded by climate change (higher temperatures and reduced rainfall) and deteriorating groundwater conditions (depth and salinity). This has created unfavorable conditions for all life-history stages of the dominant floodplain tree (Eucalyptus camaldulensis Dehnh.). Lack of extensive flooding has led to widespread dieback across the Murray River floodplain (currently 79% by area). Management for timber resources has altered the structure of these forests from one dominated by large, widely spreading trees to mixed- aged stands of smaller pole trees. Reductions in numbers of birds and other vertebrates followed the decline in habitat quality (hollow-bearing trees, fallen timber). Restoration of these forests is dependent on substantial increases in the frequency and extent of flooding, improvements in groundwater conditions, re-establishing a diversity of forest structures, removal of grazing and consideration of these interacting stressors.