Southeast Asia was almost entirely covered by rainforest 8,000 years ago. Today, this region is experiencing the highest relative rates of deforestation and forest degradation in the humid tropics. Every year, millions of hectares of tropical forests are destroyed and degraded. Given the rapid rate of deforestation and the high concentration of endemic species in the region, Southeast Asia could lose 13–42% of local populations by the turn of the next century, at least 50% of which could represent global species extinction. In this Special Issue, we discuss the uniqueness of Southeast Asian biodiversity, drivers of forest destruction, threats to the region’s unique ecosystems and taxa, and key conservation challenges to provide a broad-based review of the science, management and policy issues concerning biodiversity conservation. Overall, we highlight the need for an interdisciplinary and multi-pronged strategy requiring all major stakeholders to work together to achieve the ultimate goal of reconciling biodiversity conservation and human well-being in the region.