Regulating the switch between proliferation and differentiation of mesenchymal stem cells is critical for the development of normal tissues, and the prevention of tumors. How mesenchymal stem cells exit from the cell cycle and differentiate into alternative cell fates such as bone, fat, and muscle, is incompletely understood. We recently discovered that a WW domain-containing molecule, TAZ, functions as a transcriptional modulator to stimulate bone development while simultaneous blocking the differentiation of mesenchymal stem cells into fat. These developmental effects occur through direct interaction between TAZ and the transcription factors Runx2 and PPARgamma, resulting in transcriptional enhancement and repression, respectively of selective programs of gene expression. We propose that TAZ, as well as a highly related molecule YAP, are functionally, though not structurally, similar to beta-catenin and integrate extracellular, membrane, and cytoskeletal-derived signals to influence mesenchymal stem cell fate.