During early limb development several signaling centers coordinate limb bud outgrowth as well as patterning. Members of the T-box gene family of transcriptional regulators are crucial players in these processes by activating and interpreting these signaling pathways. Here, we show that Tbx15, a member of this gene family, is expressed during limb development, first in the mesenchyme of the early limb bud, then during early endochondral bone development in prehypertrophic chondrocytes of cartilaginous templates. Expression is also found in mesenchymal precursor cells and prehypertrophic chondrocytes, respectively, during development of skeletal elements of the vertebral column and the head. Analysis of Tbx15 null mutant mice indicates a role of Tbx15 in the development of skeletal elements throughout the body. Mutants display a general reduction of bone size and changes of bone shape. In the forelimb skeleton, the scapula lacks the central region of the blade. Cartilaginous templates are already reduced in size and show a transient delay in ossification in mutant embryos. Mutants show a significantly reduced proliferation of prehypertrophic chondrocytes as well as of mesenchymal precursor cells. These data suggest that Tbx15 plays an important role in the development of the skeleton of the limb, vertebral column and head by controlling the number of mesenchymal precursor cells and chondrocytes.