The fusion of two membrane compartments into a single continuous bilayer is fundamental for diverse biological processes including bacterial reproduction, gametes fertilization, virus internalization, and vesicular transport. Although all forms of membrane fusion share common mechanisms, different fusion events employ distinct molecular machineries. Membrane fusion along the secretory and endocytic pathways is driven by different SNARE protein complexes consisting of t-SNAREs on the target membrane and v-SNAREs on the transport vesicle. The assembly of cognate v- and t-SNAREs induces the formation of trans-SNARE complexes or SNAREpins, in which four SNARE motifs assemble as a twisted parallel four-helix bundle that brings opposing membranes close together and catalyzes their fusion. Pairing of distinct SNAREs and assembly of functional SNAREpins are employed by different membrane-trafficking events.