Forty years after the first clinical report on the effectiveness of chlorpromazine in psychiatric patients, neuroleptic drugs are still the most widely used drugs in the treatment of schizophrenia. Indeed, there are no other drugs which have proven to be as effective in the treatment of this severe psychiatric disorder. Yet, there are still many unresolved problems relating to neuroleptic drugs. The present review gives a comprehensive overview of our knowledge (and our lack of knowledge) with respect to the clinical and preclinical effects of neuroleptic drugs and tries to integrate this knowledge in order to identify the neuronal mechanisms underlying the therapeutic and side effects of neuroleptic drugs.