Secretion is a fundamental cellular process used by all eukaryotes to insert proteins into the plasma membrane and transport signaling molecules and intravesicular proteins into the extracellular space. Secretion requires the fusion of two phospholipid bilayers within the cell, an energetically unfavorable process. A conserved repertoire of vesicle-trafficking proteins has evolved that function to overcome this energy barrier and temporally and spatially control membrane fusion within the cell. Within neurons, opening of synaptic calcium channels and subsequent calcium entry triggers synchronous synaptic vesicle exocytosis and neurotransmitter release into the synaptic cleft. After fusion, synaptic vesicles undergo endocytosis, are refilled with neurotransmitter, and return to the vesicle pool for further rounds of cycling. It is within this local synaptic trafficking pathway that the synaptotagmin family of calcium-binding synaptic vesicle proteins has been postulated to function. Here we review the current literature on the function of the synaptotagmin family and discuss the implications for synaptic transmission and membrane trafficking.