Classic galactosemia is an enigmatic disorder that presents the challenge of unraveling the basis of the long-term complications of mental disability, speech defects, ovarian failure and neurologic syndromes which occur despite a galactose-restricted diet. A complete understanding of the pathobiochemistry and molecular genetics, and evaluation of the present theories for the poor long-term outcome, continuous intoxication, critical metabolite depletion and in utero damage is needed in order to design new therapeutic strategies. Answering this urgent question of how to treat galactosemic patients mandates enhanced clinical and basic research efforts.