Which genes are responsible for controlling bone density? This is a question that Kaare Gautvik and colleagues address on p. 2782, where they shed new light on the mechanisms of osteoporosis. The researchers suspected that the transcription factor Sox4 might have a role in bone formation – they knew that other Sox genes regulate chrondrocyte and osteoblast differentiation and they had previously shown that Sox4 is expressed in skeletal tissue. To test the possibility, they made Sox4–/+ heterozygous mice (homozygous Sox4– mice die as embryos) and measured aspects of their bone density and strength. These heterozygotes have osteopenia – reduced bone density – and reduced bone strength compared with their wild-type counterparts. Probing the molecular mechanisms underlying these phenotypes in osteoblast cell cultures, Gautvik and colleagues found that, without Sox4, proliferation, differentiation and mineralization are all inhibited. Furthermore, cells lacking Sox4 display reduced expression of Osterix (a protein crucial for osteogenesis), although, curiously, expression of Runx2 (which has been shown to function upstream of Osterix) is not affected. The researchers conclude that Sox4 is crucial for osteoblast proliferation and differentiation and that it functions upstream of Osterix but independently of Runx2.