Bone is a highly mechanosensitive tissue that adapts its function in response to mechanical cues. These cues are converted into biomechanical signals that regulate osteogenic gene expression through mechanotransduction. Bone homeostasis and the long-term bone adaptation to its mechanical environment depend on the proper integration of mechanical signals with transcriptional programs that regulate osteogenesis. Runt-related transcription factor 2 (RUNX2) is a pioneer transcription factor, a mechanosensitive molecule, which coordinates osteoblast differentiation and bone remodeling. RUNX2 activity in mechanically induced environments is subject to epigenetic regulation. Mechanical cues modulate RUNX2 through epigenetic mechanisms, including DNA methylation, histone modifications, chromatin remodeling, and non-coding RNAs. Proper epigenetic coordination ensures the stability of osteogenic gene expression. Any disruption of this mechanotransduction-epigenetic route leads to bone diseases such as osteoporosis, osteoarthritis, and dysfunctional fracture repair. Moreover, epigenetic reprogramming of RUNX2 is increasingly evident in bone tumors, particularly osteosarcoma, where aberrant RUNX2 activity is associated with cell proliferation, tumor progression, survival, metastasis, and loss of differentiation. This chapter examines current evidence on RUNX2 epigenetic regulation in response to mechanical forces, discusses how its orchestration relates to bone disease and bone tumor development, and underscores potential therapeutic opportunities that arise from targeting specific epigenetic mechanisms.