Osteogenic differentiation of skeletal stem cells is an integral part of bone development and homeostasis, and the perturbation of this process is one of the causes to skeletal disease. Understanding of how epigenetic events regulate skeletal stem cell differentiation is therefore of great importance. While the basic epigenetic modifications leading to bone formation are somewhat under explored, a significant amount of research has defined the regulatory roles of histone modifications in osteogenic differentiation. The orchestration of histone modifications is a requirement to establish the epigenetic status which regulates gene transcription during osteogenic differentiation of skeletal stem cells. Here we focus on the roles of histone modification during osteogenic differentiation and review studies that have advanced our knowledge in the field. Before this summary, a brief description is given regarding the up-to-date understanding of the definition of skeletal stem cells and the main mechanisms responsible for histone modifications.