Fusion between opposing cellular membranes is essential for numerous cellular activities such as protein maturation, neurotransmission, hormone secretion, and enzyme release. The universal molecular mechanism of membrane fusion involves Ca(2+), and the assembly of a specialized set of proteins present in the opposing membrane bilayers. For example in cell secretion, target membrane proteins at the cell plasma membrane SNAP-25 and syntaxin termed t-SNAREs, and secretory vesicle-associated protein VAMP or v-SNARE, are part of the conserved protein complex involved in fusion of opposing membranes. In the presence of Ca(2+), t-SNAREs and v-SNARE in opposing bilayers interact and self-assemble in a ring conformation, to form conducting channels. Such self-assembly of t-/v-SNARE ring occurs only when the respective SNAREs are in association with membrane. The size of the SNARE ring complex is dependent on the curvature of the opposing bilayers. Electron density map and 3-D topography of the SNARE ring complex, suggests the formation of a leak-proof channel measuring 25 Å in ring thickness, and 42 Å in height. The mechanism of membrane-directed SNARE ring complex assembly, and the mathematical prediction of SNARE ring size, has been determined. X-ray diffraction measurements and simulation studies have further advanced that membrane-associated t-SNAREs and v-SNARE overcome repulsive forces to bring the opposing membranes close to within a distance of approximately 2.8 Å. Calcium is then able to bridge the closely apposed bilayers, leading to the release of water from hydrated Ca(2+) ions as well as the loosely coordinated water at phospholipid head groups, leading to membrane destabilization and fusion.