During the last decade a considerable amount of data have been accumulated regarding the role of intracellular signaling pathways in the pathogenesis of human diseases. One of these, Notch signaling, well known for its significance in cellular development and tissue morphogenesis, has been increasingly recognized as a crucial participant in the pathogenetic mechanisms underlying certain skeletal disorders. A better understanding of the biology and regulation of this multifaceted pathway is considered an important step towards clarification of the pathogenesis of various skeletal diseases and the development of novel targets for therapeutic purposes.