How reproductive isolation is established between populations is a fundamental question in the study of speciation. To answer this question, mechanisms of prezygotic and postzygotic isolation have been analyzed in many species pairs from diverse taxa. Because of its genetic manipulability, the genus Drosophila is suitable for such analyses. Since hybrid inviability and sterility was noticed in crosses between Drosophila melanogaster and Drosophila simulans 90 years ago, this species pair has contributed much to our knowledge of genetic mechanisms of reproductive isolation. The history of genetic analyses of postzygotic isolation in this species pair is reviewed here.