Synaptotagmin I belongs to a family of C2 domain containing proteins, which include Synatotagmin II to XI and Srg1. All of the members of this protein family contain a single transmembrane region and two copies of an internal repeat that is homologous to the regulatory region of Protein Kinase C (C2A and C2B domains). Synaptotagmin I-V and IX-XI are found in brain, while synaptotagmin VI-VIII are found in non-neuronal tissues. Synaptotagmin I and II have regulatory roles in synaptic vesicle docking and fusion with the plasmalemma. Both synaptotagmin I and II act as vSNAREs that form a complex with SNAP-25 and syntaxin at the plasma membrane. This complex is required for rapid, calcium-dependent synaptic vesicle exocytosis. In addition to their roles in exocytosis, synaptotagmin I and II can bind to calcium channels, calmodulin, and the clathrin adaptor protein AP-2. Synatotagmins III, V, VI, and X cannot bind IP4 like other synaptotagmins, but like most synaptotagmins these family members form heteromers with other synaptotagmins. Synaptotagmins IV, X, and Srg1 may regulate vesicular trafficking during brain development and plasticity. In neuronal and non-neuronal tissues, synaptotagmins may be important for vesicle exocytosis, endocytosis, and trafficking, as well calcium signaling.