Sex-related differences characterize multiple sclerosis, an autoimmune, inflammatory and neurodegenerative disease displaying higher incidence in females as well as discrepancies in susceptibility and progression. Besides clinical specificities, molecular and cellular differences related to sex hormones were progressively uncovered improving our understanding of the mechanisms involved in this disabling disease. The most recent findings may give rise to the identification of novel therapeutic perspectives that could meet the urgent need for a treatment preventing the transition from the recurrent- to the progressive form of the disease. The present review is an update of our current knowledge about progestagens, androgens and estrogens in the context of CNS demyelination including their synthesis, the impact of their dysregulation, the preclinical and clinical data presently available, the main molecular dimorphisms related to these hormones and their age-related changes and relationship with failure of spontaneous remyelination, likely impacting the inexorable progression of multiple sclerosis towards irreversible disabilities.