<p>Bone is a complex structure formed by cancellous and cortical bone compartments. Whereas cancellous bone remodeling has been studied extensively, less is known about mechanisms that lead to cortical bone formation and homeostasis. Corticalization is a poorly understood process, when newly formed trabeculae coalesce to consolidate as cortical bone in early life, but with an impact on skeletal integrity that is sustained throughout life. Failure to form cortical bone results in pronounced skeletal fragility, although the process is poorly understood. Mouse models of <i>Sp7</i>, <i>Itgb3</i>, <i>Socs3</i> and <i>Clcn7</i> inactivation exhibit impaired corticalization and cancellous bone osteopetrosis. The relationship between the two events has not been established. Notch receptors (1 through 4) are critical determinants of cell differentiation and function in the skeleton. NOTCH3 is structurally distinct and has a well-defined pattern of cellular expression, in smooth muscle vascular cells and osteocytes, conferring this Notch receptor a unique role in physiology. Mouse models expressing the biological active NOTCH3 intracellular domain (N3ICD) in <i>Bglap</i>^<i>+</i> osteoblasts and <i>Dmp1</i>^<i>+</i> osteocytes do not form cortical bone and display skeletal fragility, increased intracortical remodeling and cortical porosity, reflecting a bone structure that failed to mature. The mechanism may involve suppression of <i>Sp7</i> and induction of granzyme B. In conclusion, corticalization is a poorly understood process that is essential to maintain skeletal integrity and with lifelong impact on bone health.</p>