Hormonal treatment represents the principal aspect of clinical management of people with disorders of sex development (DSD) from adolescence onwards. In fact, individuals with DSD may require sex steroid replacement to induce secondary sex characteristics, to optimize bone mass accrual, and to promote physical and social well-being. Testosterone is the main hormone for treatment in males and estrogens in females. The optimal regimens for sex steroid substitutive therapy in subjects with DSD should be better defined in multi-center prospective studies. Bone health remains a crucial aspect in the management of these persons, but few sound data are available to guide clinical practice.