Neurotransmitter release is mediated by the fusion of synaptic vesicles with the pre-synaptic plasma membrane. Fusion is triggered by a rise in the intracellular calcium concentration and is dependent on the neuronal SNARE complex. A plethora of molecules including the synaptotagmins act along with the SNARE complex to enable calcium regulated synaptic vesicle exocytosis. The synaptotagmins are localized to synaptic vesicles by an N-terminal transmembrane domain and contain two cytoplasmic C2 domains. Members of the synaptotagmin family are thought to translate the rise in intracellular calcium concentration into synaptic vesicle fusion. The C2 domains of synaptotagmin-1 bind membranes in a calcium-dependent manner. We have shown that in response to calcium-dependent membrane binding synaptotagmin induces a high degree of membrane curvature. Curvature induction is required for its ability to trigger membrane fusion in vitro and in vivo. Furthermore, we now show that members of the soluble Double-C2 domain (DOC2) protein family display calcium- dependent membrane curvature induction and SNARE complex binding. Both activities are required to stimulate SNARE- dependent membrane fusion in vitro. In vivo DOC2 proteins are calcium sensors for spontaneous neurotransmitter release. Taken together these data suggest that C2 domain proteins such as the synaptotagmins and DOC2s promote membrane fusion by the induction of membrane curvature in the vicinity of the SNARE complex. Given the widespread expression of C2 domain proteins in secretory cells it is proposed that promotion of SNARE-dependent membrane fusion by the induction of membrane curvature is a widespread phenomenon.