The authors describe 40 years of antipsychotic drug research with Dr. Paul Janssen, which they have witnessed for a large part from first hand experience. The article describes the start of the Janssen Research and its early successes with antispasmodics and analgesics. The discovery of haloperidol followed from a serendipitous transition from analgesics to antipsychotics and culminated with the historical International Symposium on Haloperidol that was held in Beerse (Belgium) in 1959. The concept of the central role of dopamine receptor binding in schizophrenia has played a decisive part in focusing the Janssen Research on antipsychotics. Paul Janssen did not rest with haloperidol (CAS 52-68-8), but expanded it into the family of butyrophenone antipsychotics, using Haase's handwriting test to clinically characterize the analogues. The emerging significance of serotonin antagonism in schizophrenia is discussed in the light of the discovery of pipamperone (CAS 1893-33-0), a forerunner of the modern so-called atypical neuroleptics. Continued research produced a novel chemical family of neuroleptics, exemplified by pimozide (CAS 2062-78-4) and fluspirilene (CAS 1841-19-6), and yielded selective serotonin 5HT2-antagonists. This research ultimately led to the discovery of risperidone (CAS 106266-06-2) and paliperidone (CAS 144598-75-4), compounds with inbuilt dopamine and serotonin antagonism. The authors discuss the lack of inhibition as a common trait of stereotyped behaviour in schizophrenia and the means of determining it by means of a computerized version of Bente's button press test. Finally the appropriate use of antipsychotics for optimal therapeutic result with minimal side effects is advocated.