The insulin-like growth factor (IGF)/insulin signalling pathway regulates cell proliferation, differentiation, aging and life span. During embryonic development, transcription of the mouse and human Igf2 gene is tightly regulated by four alternative promoters whose specific roles are unclear. Now, Sylvie Nathalie Hardouin and colleagues reveal that the transcriptional activity of one of these promoters, Igf2-P2, regulates mesenchymal stem cell differentiation and osteogenesis in mice (see p. 203). The researchers show that Igf2-P2 loss-of-function mice, in which a lacZ-neo cassette replaces the P2-driven transcriptional unit of Igf2, have short, thin, poorly mineralised bones and exhibit altered bone remodelling. These abnormalities are associated with decreased numbers of embryonic mesenchymal chondroprogenitors, adult mesenchymal stem cells and osteoprogenitors. Together, these and other results support a model in which the transcriptional activity of the Igf2-P2 promoter regulates the fate of mesenchymal progenitors during bone development and adult bone remodelling, and regulates osteogenesis through its effects on both osteoprogenitors and their microenvironment.