Epithelial–mesenchymal interactions underlie the foundation for ectodermal appendage formation. Signal molecules such as BMPs and WNTs mediate crosstalk between the two tissue layers and coordinate both the induction and morphogenesis of ectodermal appendages. Here, we analyzed the function of two BMP downstream transcription factors, Msx2 and Foxn1, in nail differentiation. First, we show that Msx2 function is required during onychocyte (nail cell) terminal differentiation. Second, the Msx2/Foxn1/hair keratin pathway controlling hair differentiation is also conserved during onychocyte differentiation. Finally, the Msx2−/−; Foxn1−/− double-mutant nails exhibit a more severe phenotype than either single mutant including nail bed hyperplasia. Together, our data implicate important functions for Msx2 and Foxn1 in regulating differentiation of the keratogenous zone, proliferation of distal nail matrix cells, and organization of the nail bed. genesis 49:449–459, 2011. © 2011 Wiley-Liss, Inc.