Disorders of sexual differentiation (DSDs) presenting during adolescence are discussed, and molecular explanations are given for some. DSD conditions are often discovered during early adolescence, an age well known to predispose to high risk for adjustment problems. Presentation may be with lack of or minimal pubertal development, lack of menarche, vaginal, uterine, or breast agenesis and inappropriate sexual development such as virilization in females or feminization (gynecomastia) in males. Most such disorders require life-long therapy, with many of the medical, surgical and psychological aspects of management being accentuated during adolescence. Regardless of the age at presentation, all require skillful management to promote normal health and well-being. This care ideally involves specialists in endocrinology and medical therapy, psychology and, if required, surgery. A brief discussion of the needs of the adolescent with DSDs is presented.