“To know it is to grow it” is a central tenet in microbiology. However, very few microorganisms from deep subsurface environments or other ‘extreme’ habitats are currently in culture. A successful strategy for us has been to design growth media based on detailed, in situ geochemistry. This has led to the isolation, full characterization, and publication of several novel taxa: Palaeococcus helgesonii, a hyperthermophilic archaeon from a geothermal well in Italy; Thermogladius shockii, a new hyperthermophilic archaeal genus from a hot spring in Yellowstone National Park; Burkholderia insulsa, a chemolithotrophic bacterium from arsenic-rich shallow-sea hydrothermal sediments in Papua New Guinea; and Bacillus rigiliprofundi, an endospore-forming, Mn-oxidizing halophilic bacterium from the deep subseafloor basaltic crust in the south-west Pacific Ocean. Projects are currently underway to culture and characterize several new taxa, including ones from arsenic-rich sediments on Milos Island (Greece), the former Homestake gold mine in South Dakota, and a deep well near Death Valley. Funded by several NSF and NASA grants, we’re hoping to identify several model organisms for the deep subsurface.