Southeast Asia (SE Asia) is a known global hotspot of biodiversity and endemism, yet the region is also one of the most biotically threatened. Ecosystems across the region are threatened by an array of drivers, each of which increases the probability of extinction of species in a variety of ecosystems. These issues are symptomatic of the issues that face the global tropics; however, with around 4 billion people in the wider region and the associated pressures on biodiversity, this region may be under some of the greatest levels of biotic threat. Deforestation rates in SE Asia are some of the highest globally, additionally Southeast Asia has the highest rate of mining in the tropics, the around the greatest number of hydropower dams under construction, and a consumption of species for traditional medicines which is a threat to biodiversity globally. In this review, the greatest threats to regional biodiversity in the SE Asian region are discussed. Tree-plantations and deforestation represents one of the most imminent threats, and some countries have already lost over half their original forest cover (i.e., the Philippines, parts of Indonesia), with projections of as much as 98% loss for some regions in the coming decade. Hunting and trade represents a significant threat as demand stems not only for food, but also for medicine, for ornamentation, and as a status symbol. Mining represents a frequently overlooked threat, as the Asian region is one of the greatest exporters of limestone and various minerals globally, and the cost of this to biodiversity is not only through the direct loss of areas for mines, but also through the development of roads that further fragment the landscape, the leakage of heavy metals, and the destruction of limestone karsts, which represent global endemicity hotspots. Reservoir construction, wetland drainage, fires, pollution, invasive species, disease, and finally climate change are also considered. Once each issue has been discussed, the overall prognosis of regional biodiversity and priority actions to protect SE Asian biodiversity in the future is discussed.