P lacental cells of mesenchymal origin were used to study the regulation of fetal growth at the cellular level. A significant difference in the in vitro growth rates of placental fibroblasts was observed as a function of gestational age. Cells derived from 10-19-wk placentae exhibited proliferative rates two to three times greater than cells derived from 7-9-wk placentae (16-30 h vs. 30-60 h, P less than 0.001). The proliferation rate remained stable throughout multiple passages in culture. Additionally, these two groups of cell strains exhibited marked differences in their responsiveness to mitogenic stimuli. Using maximal effective concentrations, insulin-like growth factor I interacted synergistically with epidermal growth factor and fibroblast growth factor to stimulate DNA synthesis in cells derived from 10-19-wk placentae. By contrast, the interaction of insulin-like growth factor 1 with epidermal growth factor and fibroblast growth factor exhibited significantly less synergy in 7-9-wk cells. These findings argue that the accelerated growth rate of human fetal cells results primarily from developmental events intrinsic to the cells and is associated with enhanced responsiveness to the mitogenic action of peptide growth factors.