Abstract: In eukaryotic cells, SNARE proteins of the vesicle or target membrane (v- or t-SNAREs) play a central role in the control of membrane fusion and protein and lipid traffic. SNAREs’ coiled-coil domains (CCDs) have probably evolved from a common ancestor with a hydrophobic heptad register, interrupted by a conserved polar residue at the ionic “zero” layer. Depending on the nature of such residue, SNAREs have been reclassified as either Q- or R-SNAREs. R-SNAREs consist of two subfamilies: (i) short VAMPs or brevins (from the latin word “brevis” = short), and (ii) long VAMPs or longins, sharing a conserved N-terminal Longin Domain. Distinct amino acid patches are likely to determine specificity of SNARE pairing by reducing structural integrity when mismatched SNAREs interact. When considering pairing of the Q- and R-SNARE CCDs, an asymmetric ‘‘complementarity’’ is found in layers -3, -2, and +6, where bulky side chains are packed together with smaller ones, possibly enforcing the correct register between the CCDs of the fusion complex. Sequence variation in the SNARE domains, by altering local charges at the interaction layers, is likely to mediate a fine modulation of the interaction specificity and/or kinetics, regulating intramolecular binding as well as binding to a growing family of SNARE-interacting factors. Although the structure of the SNARE complex is evolutionarily conserved, biological specificity is probably mediated mainly by accessory proteins recognizing different CCD surface patterns of charges, polar and nonpolar side chains different between the endosomal and neuronal complexes. Recently, it has been reported that the interaction among acidic surface residues from the SNAREs and basic residues over the concave surface of α-SNAP is crucial to the disassembly of the complex.