Twenty years of research have led to the model, acknowledged by the 2013 Nobel Prize in Physiology and Medicine, that soluble N -ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) mediate the fusion of intracellular membranes. SNAREs are also able to recruit other molecules playing essential roles in the spatial and temporal regulation of vesicular traffic, and they now even appear as multitask proteins in intracellular vesicle biogenesis, transport and fusion. Here we focus on recent findings at the molecular level which suggest how SNAREs operate as membrane fusion nanomachines that are finely tuned to allow fusion to occur at the right time and place, and how they are integrated into complex molecular networks of interaction.