Runx2 is a key transcriptional modulator of osteoblast differentiation that plays a fundamental role in osteoblast maturation and homeostasis. Runx2-null mice despite normal skeletal patterning have no osteoblasts and consequently bone tissue. Mutations of the runx2 gene in humans cause cleidocranial dysplasia. As a member of the Runx family of transcription factors, Runx2 operates by binding to the osteoblast-specific cis-acting element 2 (OSE2), which is found in the regulatory region of all main osteoblast-related genes controlling their expression. Its expression and/or activity are dictated by a number of different external cues while multiple signalling pathways that affect osteoblast function merge to and are integrated by Runx2. Among the various stimuli that modulate Runx2 activity, mechanical loading (strain/stretching) has been revealed to be one of the most critical signals that connect Runx2 with osteoblast function and bone remodelling through mechanotransduction.