The discovery of clozapine represents such a combination of paradoxes, luck and unfortunate incidents that some people believe the history of clozapine should be entitled "The Clozapine Story" (Stille and Fischer-Cornelssen 1988). One paradox lies in the fact that clozapine is at the same time a very old drug and also one of the newest and most modern psychotropics. Clozapine was first investigated in Europe in the mid-1960s by Austrian and German clinicians, who described it as a potent antipsychotic drug (Bente et al. 1966; Gross and Langner 1966); clozapine was then discovered a second time in the 1980s by clinicians in the United States. Now clozapine is judged to be a drug of the future a real pioneer in the treatment of schizophrenia. Some pharmacologists even now point out that clozapine is not a neuroleptic drug, because it has never shown the typical pharmacological profile or extrapyramidal sideeffects of the so-called classical neuroleptics, such as haloperidol. In contrast, other pharmacologists consider clozapine to be a pioneering drug because it refutes the hypothesis of a connection between clinical efficacy and extrapyramidal effects. From the point of view of stereochemistry, it was expected that clozapine would have an antidepressant effect but it has an antipsychotic effect! Over a period of years the manufacturers of clozapine were more interested in stopping rather than in broadening its use ! Taking all of these paradoxes into consideration, it is impossible to give an objective summary of the history of clozapine. I am only able to describe subjectively some aspects of "The Clozapine Story", on the one hand based on my experience with the clinical use of clozapine in the university hospitals in Berlin and Munich over a period of almost 25 years and, on the otherhand, based on research done since 1971 by Ackenheil, Matussek, R~ther and other members of the Department of Psychiatry of the University of Munich. Initial interest in a drug such as clozapine arose from speculations and possible connections between chemical structure and therapeutic effectiveness. After the discovery of imipramine by Kuhn in 1957, the molecules of all pharmacologically defined and clinically applied tricyclic psychotropic drugs were built as ,'~ calotte models" in the Research Department of the Psychiatric Department of the Free University of Berlin. This was done in the manner proposed by Pauling and, in retrospect, this method was a very naive and old-fashioned procedure. The aim was to discover consistent differences between neuroleptic and antidepressant drugs and by this procedure to develop a new method for drug-screening independent of pharmacological screening (Bente et al. 1964). At that time, we came to the conclusion that the angle between the planes of the rings of tricyclic drugs was flat, and that the drug should have a neuroleptic profile. I f the angle was sharper and the planes of the rings twisted relative to each other, the drug should have an antidepressant effect (Fig. 1). These speculations, which in hindsight seem strange, were published at the beginning of the 1960s. The summary of this work, published in 1964 (Bente et al. 1964), resulted in us having a number of discussions with chemists and pharmacologists, including a chemist and a pharmacologist from a company based in Berne, Switzerland (Wander). These scientists offered us a group of newly developed tricyclic drugs with a 7-membered central ring. Given the stereostructure of these molecules, all of these drugs should have been antidepressants. The first drug investigated in this group, a dibenzapine, was an antidepressant, which is still a very reliable antidepressant used widely in the clinical setting (Bente et al. 1966a). Investigation of other drugs appeared to confirm our theory concerning the connection between chemical structure and therapeutic profile. However, clinical investigation of three compounds produced by Wander completely undermined our theory. As far as the chemical structure was concerned, the drugs should have been antidepressants, but clinical investigations showed them to be neuroleptics. We reported these findings on the three compounds at the