Fibroblast growth factor receptor 3 (FGFR3) plays an important role in the control of chondrocyte proliferation and differentiation, a process critical for normal development of the skeleton. To reveal the contributions of the epithelial Fgfr3b isoform and the mesenchymal Fgfr3c isoform to skeletal overgrowth seen in mice, in which both isoforms have been inactivated (Fgf3c(-/-) mice), we have generated mice in which each of the two Fgfr3 isoforms has been selectively inactivated. Whereas no apparent phenotype was detected in Fgfr3b(-/-) mice, strong stimulation of chondrocyte proliferation in the growth plates of Fgf3c(-/-) mice caused dramatic skeletal overgrowth and other skeletal abnormalities resembling the phenotype of mice deficient in both Fgfr3 isoforms. In addition, Fgfr3c(-/-) mice exhibited decreased bone mineral density in the cortical and trabecular bone, whereas the bone mineral density of Fgfr3b(-/-) mice resembled that of WT mice. These experiments demonstrated that the mesenchymal Fgfr3c isoform is responsible for controlling chondrocyte proliferation and differentiation that mediate normal skeletal development, whereas the epithelial Fgfr3b isoform does not contribute toward this process.