Secretory vesicle swelling has been demonstrated to be a requirement in cell secretion. In the past 25 years, the quest to elucidate the molecular mechanism of secretory vesicle swelling, serendipitously revealed the presence of water channels or aquaporins at the secretory vesicle membrane and their involvement in rapid gaiting of water into secretory vesicles and their swelling during secretion. These studies further provided an understanding of aquaporin regulation at the secretory vesicle membrane. Secretory vesicles within live cells, isolated secretory vesicles, single vesicle electrophysiological patch clamp studies and the swelling complex reconstituted into liposomes, have all been utilized to elucidate the mechanism and regulation of secretory vesicle swelling. Results from these studies collectively demonstrate the involvement of β-adrenergic receptor, heterotrimeric GTP-binding G-proteins such as GαI; PLA2 and potassium and chloride channels, in the regulation of aquaporins at the secretory vesicle membrane.