Cells synthesize and store within membranous sacs products such as hormones, growth factors, neurotransmitters, or digestive enzymes, for release on demand. As recently as just 15 years ago, it was believed that during cell secretion, membrane-bound secretory vesicles completely merge at the cell plasma membrane resulting in the diffusion of intravesicular contents to the cell exterior and the compensatory retrieval of the excess membrane by endocytosis. This explanation, however, failed to explain the generation of partially empty vesicles observed in electron micrographs following secretion. Logically therefore, in a 1993 News and Views article in the journal Nature, Prof. Erwin Neher wrote "It seems terribly wasteful that, during the release of hormones and neurotransmitters from a cell, the membrane of a vesicle should merge with the plasma membrane to be retrieved for recycling only seconds or minutes later." The discovery of permanent secretory portals or nanomachines at the cell plasma membrane called POROSOMES, where membrane-bound secretory vesicles transiently dock and fuse to release intravesicular contents to the cell exterior, has finally resolved this conundrum. Following this discovery, the composition of the porosome, its structure and dynamics visualized with high-resolution imaging techniques atomic force and electron microscopy, and its functional reconstitution into artificial lipid membrane have provided a molecular understanding of cell secretion. In agreement, it has been demonstrated that "secretory granules are recaptured largely intact after stimulated exocytosis in cultured endocrine cells" (Proc Natl Acad Sci U S A 100:2070-2075, 2003); that "single synaptic vesicles fuse transiently and successively without loss of identity" (Nature 423:643-647, 2003); and that "zymogen granule exocytosis is characterized by long fusion pore openings and preservation of vesicle lipid identity" (Proc Natl Acad Sci U S A 101:6774-6779, 2004). It made no sense all these years to argue that mammalian cells possess an "all or none" mechanism of cell secretion resulting from complete vesicle merger at the cell plasma membrane, when even single-cell organisms have developed specialized and sophisticated secretory machinery, such as the secretion apparatus of Toxoplasma gondii, contractile vacuoles in paramecium, and different types of secretory structures in bacteria. The discovery of the porosome and its functional reconstitution in artificial lipid membrane, and an understanding of its morphology, composition, and dynamics, has resulted in a paradigm shift in our understanding of the secretory process in cells.