Interactions between epithelium and mesenchyme are common features of early stages of morphogenesis in different organs. In this historical review article, we retrospectively analyze the most important contribution to the definition and characterization of these interactions in three different organogenetic systems, including kidney, lung and limb bud. Tubule formation in the kidney is an example of an organogenetic event which involves interaction between the ureteric epithelium and the underlying mesenchyme that, in turn, induces the branching of the ureteric epithelium. In contrast, in lung organogenesis, interactive signaling occurs between the endodermal epithelium and the mesenchyme, leading to an alveolar structure. Finally, limb bud development results from a series of epithelial-mesenchymal interactions between the mesenchymal cells of the lateral plate mesoderm and the overlying ectodermal cells.