Southeast Asia has the highest relative rate of deforestation of any major tropical region, and could lose three quarters of its original forests by 2100 and up to 42% of its biodiversity. Here, we report on the current state of its biota and highlight the primary drivers of the threat of extinction now faced by much of the unique and rich fauna and flora of the region. Furthermore, the known impacts on the biodiversity of Southeast Asia are likely to be just the tip of the iceberg, owing to the paucity of research data. The looming Southeast Asian biodiversity disaster demands immediate and definitive actions, yet such measures continue to be constrained by socioeconomic factors, including poverty and lack of infrastructure. Any realistic solution will need to involve a multidisciplinary strategy, including political, socioeconomic and scientific input, in which all major stakeholders (government, non-government, national and international organizations) must participate.