THE proto-oncogene c-fos is the cellular homologue of v-fos originally isolated from murine osteosarcoma¹. Fos protein is a major component of the AP-1 transcription factor complex, which includes members of the jun family². Stable expression of c-fos in mice has been demonstrated in developing bones and teeth, haematopoietic cells, germ cells and in the central nervous system^3–11. It has been proposed that c-fos has an important role in signal transduction, cell proliferation and differentiation^12–15. We have previously demonstrated that overexpression of c-fos in transgenic and chimaeric mice specifically affects bone, cartilage and haematopoietic cell development^16–20. To understand better the function of c-fosin vivo, we used gene targeting in embryonic stem cells to generate cells and mice lacking c-fos. Here we report that heterozygous fos +/− mice appear normal, although females exhibit a distorted transmission frequency. All homozygous fos −/− mice are growth-retarded, develop osteopetrosis with deficiencies in bone remodelling and tooth eruption, and have altered haematopoiesis. These data define the c-Fos protein as an essential molecule for the development of specific cellular compartments.