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Six decades after the serendipitous discovery of chlorpromazine as an antipsychotic and four decades after the launch of clozapine, the first atypical or second generation antipsychotic, psychopharmacology has arrived at an important crossroad. Revealing the different modes of action of available antipsychotics on biochemical, electrophysiologic, neuroanatomic, and behavioral grounds has not only helped to develop new medications with improved tolerability but also contributed to our understanding of mechanisms relevant for psychosis in general and schizophrenia and bipolar disorder in particular. It is remarkable in this context the extent to which such research has moved towards using imaging techniques and more empirical clinical assessments. Although research targeted at specific receptors and pathways of antipsychotic drug action has extended our knowledge considerably, it remains true that all currently approved antipsychotic drugs share one common mechanism, i.e., dopamine D2 receptor antagonism. There is still uncertainty as to whether first- and second-generation antipsychotics can really be separated and if the assumed progress exemplified by newer compounds is sufficient to survive the challenges of evidence-based medicine. Although the use of antipsychotics has become safer, adverse metabolic and cardiac effects remain as major issues in the clinic and in the development of new agents. It became clear that all clinically used antipsychotic medications are effective in treating positive symptoms, but certainly not for negative symptoms and also not for the core cognitive deficits that have been widely neglected in research in the time between Kraepelin and the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) initiative.
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