Oxalobacter formigenes is part of the bacterial flora in the large intestine of humans and many other mammalian species. It is unique in that it requires oxalate both as an energy and carbon source. A lack of colonization with O. formigenes is a risk factor for idiopathic recurrent calcium oxalate stone disease. Protection against calcium oxalate stone disease appears to be due to the oxalate degradation that occurs in the gut as measurements of 24 h urinary oxalate indicate that O. formigenes colonized calcium oxalate stone formers excrete less oxalate compared to non-colonized individuals when ingesting standardized diets. There is also some evidence that suggests a possible mechanism involving intestinal oxalate secretion triggered by the bacterium itself, as O. formigenes colonization appears to lower plasma oxalate. Whether high oral doses of this organism can promote sufficient intestinal oxalate secretion to diminish the oxalate burden on the kidney in individuals with Primary Hyperoxaluria is currently being tested by OxThera, Inc. in a phase 2 clinical trial. Much still remains to be learned about how O. formigenes establishes and maintains gut colonization and the precise mechanisms by which it modifies stone risk.