The southern part of the Mekong Delta Limestones of Vietnam (MDL-HC or Hon Chong karst) comprises numerous small limestone hills. It is a hotspot of biodiversity for soil and cave invertebrates. Here, we synthesize the results of biological surveys carried out in Hang Mo So, the richest MDL-HC cave for troglobionts, and in surrounding karsts. Methodologies for the ecological characterization of species are discussed, with emphasis on parallel sampling (external soil plus cave). Hang Mo So has 27 troglobionts, including many still undescribed. An additional 40 cave-obligate species are known from other caves of MDL-HC. Among them, several are expected to be found in Hang Mo So. Most troglobionts of MDL-HC are endemic. Several relictual taxa without close relatives in Southeast Asia occur in Hang Mo So and in MDL-HC, reflecting an ancient origin of the fauna. The reasons for this richness are uncertain, but the cause of its current destruction—quarrying—is all too evident. Most of the original 4 km2 of the MDL-HC karst has been destroyed or soon will be, ultimately leaving only 1.6 km2 unquarried. Endemic species linked to karst habitats are, therefore, under clear threat of extinction. The Hon Chong karst (MDL-HC) was listed among the ten most endangered karsts on the planet 25 years ago. Today it would probably top the list.