An emerging research program on population and geographic range dynamics of Australia's mammals illustrates an approach to better understand and respond to geographic range collapses of threatened wildlife in general. In 1788, Europeans colonized an Australia with a diverse and largely endemic mammal fauna, where many species that are now extinct or threatened were common and widespread. Subsequent population declines, range collapses and extinctions were caused by introduced predators and herbivores, altered land use, modified fire regimes and the synergies between these threats. Declines in population and range size continue for many Australian mammals despite legislative protection and conservation interventions. Here, we propose an approach that integrates museum data and other historical records into process-explicit macroecological models to better resolve mammal distributions and abundances as they were at European arrival. We then illustrate how this integrative approach can identify the likely synergistic mechanisms causing mammal population declines across these and other landscapes. This emerging research approach, undertaken with fine temporal and spatial resolution, but at large geographic scales, will provide valuable insights into the different pathways to, and drivers of, extinction. Such insights may, in turn, underpin conservation strategies based on a process-explicit understanding of population decline and range collapse under alternative scenarios of impending climate and environmental change. Given that similar information is available for other regional biotas, the approach we describe here can be adapted to conserve threatened wildlife in other regions across the globe.