Mammalian palatogenesis depends on interactions between the stomodium-derived epithelium and the cranial neural crest-derived ectomesenchyme. Fibroblast growth factor 10 (FGF10) is a mesenchymal signaling factor that guides the morphogenesis of multiple organs through tissue-tissue interactions. This is consistent with widespread agenesis and dysgenesis of organs observed in Fgf10-/- mice. In this study, we report the presence of a wide-open cleft secondary palate in Fgf10 homozygous null mutant mice. Fgf10 transcripts were detected in the palatal mesenchyme from E11.5 to E13.5 during normal palatogenesis and were enriched in the anterior and middle portions of the palatal shelves. In Fgf10-/- embryos, histological analyses revealed aberrant adhesion of the palatal shelves with the tongue in the anterior and fusion with the mandible in the middle and posterior beginning at E13.5, which could prevent normal elevation of the palatal shelves leading to a cleft palate. TUNEL and BrdU assays demonstrated significant levels of apoptosis in the medial edge epithelium (MEE) but unaltered cell proliferation in mutant palatal shelves. At the molecular level, we show that Fgf10 is epistatic to Jagged2 and Tgfbeta3 in the developing palate. Notably, the expression of Jagged2 is downregulated throughout the palate epithelium in Fgf10 mutants while Tgfbeta3 is misexpressed in the palatal epithelium at the oral side. Our results demonstrate that mesenchymally expressed Fgf10 is necessary for the survival of MEE cells and for the normal expression of Jagged2 and Tgfbeta3 in the palatal epithelium during mammalian palatogenesis.