Cbfa1/Runx2 is a bone transcription factor homologous to the Drosophila protein, Runt. Runx2 is a master gene that encodes for a protein involved in the osteogenic differentiation process from mesenchymal precursors. It is known that in Cbfa1 deficient mice (Cbfa1(-/-)) the lack of mature osteoblasts is associated to incomplete bone mineralization. An important aim of modern biology is the development of new molecular tools for identification of therapeutic approaches. Recent discoveries in cell and molecular biology enabled researchers in the bone tissue-engineering field to develop new strategies for gene and cell-based therapies. This review summarizes the process of osteogenic differentiation from mesenchymal stem cells and the importance of bone regeneration is discussed. In particular, given the increasing interest in the study of the transcription factor Runx2, this review highlights the role of this target gene and addresses recent strategies using Runx2 for bone regeneration.