Due to major improvements in the management and therapy of patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency (21OHD) along childhood and adolescence, affected women are able to reach adulthood. Therefore, management throughout adult life became even more complex, leading to new challenges. Both the protracted use of corticosteroids (sometimes in supraphysiologic doses), and excess androgen (due to irregular treatment and/or inadequate dosage) may impair the quality of life and health outcomes in affected adult women, causing osteoporosis, metabolic disturbances with high cardiovascular risk, cosmetic damage, infertility, and psychosocial and psychosexual changes. However, long-term follow-up studies with 21OHD adult women are still required. In this review, we discuss some important and controversial aspects of the follow-up of adult women with 21OHD, and recommend the use of a customized multi-disciplinary therapeutic approach while further studies with these patients do not provide distinct understanding and well-defined attitudes towards better quality of life.