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Despite projections of a severe extinction event, a window of opportunity is now open for a mix of policies to avoid biodiversity collapse in the Cerrado hotspot. Brazil’s success in lowering Amazon deforestation rates by 70% from 2005 to 2013 risks becoming overshadowed by rapid clearance of the adjacent Cerrado biome. As we report here, across these 200 million hectares (Mha) of tropical savannah, a perfect storm of agribusiness expansion, infrastructure development, low legal protection and limited conservation incentives is set to trigger an extinction episode of global significance. This dismal scenario, however, can be averted. Large yield gaps in converted lands mean food production could still be greatly increased even while reducing the footprint of farming. Legal frameworks, policy instruments and multi-stakeholder agreements that largely account for the remarkable events in the Amazon are slowly being applied in the Cerrado, but must be scaled-up. Many pivotal decisions will be made in the coming months. We urge national policymakers and international stakeholders in positions to do so to rescue the Cerrado from the brink, and deliver a step change in Brazil’s progress towards sustainable development.