Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase and distributes important regulatory functions in skeletal system. Mesenchymal stem cell (MSC) possesses significant migration and differentiation capacity, is an important source of distinctive bone cells production and a prominent bone development pathway. MSC has a wide range of applications in tissue bioengineering and regenerative medicine, and is frequently employed for hematopoietic support, immunological regulation, and defect repair, although current research is insufficient. FAK has been identified to cross-link with many other keys signaling pathways in bone biology and is considered as a fundamental “crossroad” on the signal transduction pathway and a “node” in the signal network to mediate MSC lineage development in skeletal system. In this review, we summarized the structure, characteristics, cellular signaling, and the interactions of FAK with other signaling pathways in the skeletal system. The discovery of FAK and its mediated molecules will lead to a new knowledge of bone development and bone construction as well as considerable potential for therapeutic use in the treatment of bone-related disorders such as osteoporosis, osteoarthritis, and osteosarcoma.