Secretion is a universal cellular process occurring in simple organisms such as bakers yeast to complex multicellular organisms including humans. Neurotransmission, digestion, immune response, or the release of hormones, each occurs as a result of cell secretion. Cell secretion involves the transport of vesicular products from within cells to the outside. For example, when we eat digestive enzymes stored in membranous sacs or secretory vesicles in the exocrine pancreas are released from the cell following fusion of the secretory vesicle membrane at the cell plasma membrane. Similarly for neurotransmission, synaptic vesicles containing neurotransmitters are released when they fuse at the presynaptic membrane. It was therefore logical to believe that secretory vesicles fuse and completely merge and incorporate their membrane at the cell plasma membrane to enable the release of intravesicular contents from cells. In support of this mechanism of cell secretion, it was believed for nearly 50–60 years that, following stimulation of secretion, the flat cell plasma membrane (for lack of a better term at the time) invaginates toward the cytosol, eventually making contact with the secretory vesicle membrane to form the ‘fusion pore’. It was believed that the secretory vesicle then fused with the fusion pore, distending it until the vesicle membrane completely merged with the cell plasma membrane. However such a mechanism of vesicular release could not explain the accumulation of empty or partially empty vesicles following cell secretion. This conundrum was finally solved following the discovery of the ‘porosome’, the permanent cup-shaped structures at the cell plasma membrane in secretory cells where secretory vesicles transiently dock and fuse to release intravesicular contents, and with the discovery that secretory vesicle swelling is required for the regulated expulsion of secretory products during cell secretion. Today we know that following a secretory stimulus, secretory vesicles transiently fuse at the base of porosomes and release intravesicular contents dictated by the turgor pressure generated from the swelling of secretory vesicles. The amount secreted has been demonstrated to be directly proportional to the extent of vesicle swelling. The partially empty vesicle generated then dissociates from the porosome and may be available for another round of fusion, swelling, release, and dissociation at the cell plasma membrane.