The sternum is an important part of the vertebrate skeleton and serves to protect the heart and lungs. Sternum bone formation (ossification) requires the differentiation of mesenchymal stem cells in the lateral plate mesoderm (LPM) into various cell types, including bone-producing osteoblasts. Now, Atsuko Sehara-Fujisawa and colleagues provide new insight into how this process is regulated. By screening zebrafish Gal4-UAS enhancer trap lines, they identify the transcription factor Ebf3 as a candidate regulator of sternum ossification. They show that, in mice, Ebf3 is expressed in the LPM tissue of the thorax and its knockout either in the entire embryo or specifically in the LPM prevents sternum formation, although chondrogenesis is unaffected. Interestingly, the number of LPM-derived osteoblasts and pre-osteoblasts expressing regulators of osteoblast differentiation, Osx and Runx2, respectively, is reduced in the absence of Ebf3. Moreover, the authors find that Ebf3 promotes sternum ossification between embryonic days 9.5 and 10.5, immediately before the pre-osteoblast marker Runx2 is expressed in LPM cells. Accordingly, their analysis of transcripts from wild-type and Ebf3 knockout embryos reveals that mesenchymal cells in the LPM fail to differentiate towards pre-osteoblasts in the absence of Ebf3, thus precluding sternum ossification. Collectively, these results establish Ebf3 as a novel regulator of sternum ossification, opening up the door for further studies on the differentiation of LPM-derived mesenchymal cells mediated by Ebf3.