After the discovery of antipsychotic drugs, the nature of clinical practice entered a period of inexorable transition. The advances of psychopharmacotherapy have interacted in complex ways with clinical practice, and the economics and policy of mental health care systems. The study of the mechanisms of action of these drugs has guided the development of hopefully improved treatment, and stimulated biological research on the pathophysiology of severe mental disorders. Despite the considerable effort to modify and change existing antipsychotic drugs, progress has been modest. This review describes the history of antipsychotic drugs and their impact on clinical practice and the study of psychiatric disorders, and offer prospects for future developments. Although finding new knowledge and methodologies to bring innovative discovery is imperative, as of now, it is important to provide comprehensive care, including the optimal use of existing antipsychotic drugs.