Ca²⁺ triggers many forms of exocytosis in different types of eukaryotic cells, for example synaptic vesicle exocytosis in neurons, granule exocytosis in mast cells, and hormone exocytosis in endocrine cells. Work over the past two decades has shown that synaptotagmins function as the primary Ca²⁺-sensors for most of these forms of exocytosis, and that synaptotagmins act via Ca²⁺-dependent interactions with both the fusing phospholipid membranes and the membrane fusion machinery. However, some forms of Ca²⁺-induced exocytosis may utilize other, as yet unidentified Ca²⁺-sensors, for example, slow synaptic exocytosis mediating asynchronous neurotransmitter release. In the following overview, we will discuss the synaptotagmin-based mechanism of Ca²⁺-triggered exocytosis in neurons and neuroendocrine cells, and its potential extension to other types of Ca²⁺-stimulated exocytosis for which no synaptotagmin Ca²⁺-sensor has been identified.