Despite recent enormous advances in the understanding of the molecular mechanisms of sex development, the medical decisions made in patients with disorders of sex development (DSD) are mostly lacking evidence-based principles and are carried on case by case evaluations. Very critical discussions have focused on approaches on gender assignment and treatment of DSD. Any decision should be based on a correct diagnosis and possible prediction of development during puberty and adulthood of the affected individual. Puberty plays a pivotal role not only because of the physical changes induced by endogenous or supplementary steroids, but also as a time for sexual orientation and promotion of gender identity. Therefore, many aspects from psychosexual guidance to medical treatment including hormone supplementation and surgical procedures have to be considered. The patient should be fully aware of the underlying condition and should be able to reflect any therapeutically valid options. This can only be managed by a multidisciplinary team involving many subspecialties. Most of all, experienced professionalism is needed to deal with these patients.