The molecular mechanisms for calcium‐triggered membrane fusion have long been sought for, and detailed models now exist that account for at least some of the functions of the many proteins involved in the process. Key players in the fusion reaction are a group of proteins that, upon binding to calcium, trigger the merger of cargo‐filled vesicles with the plasma membrane. Low‐affinity, fast‐kinetics calcium sensors of the synaptotagmin family – especially synaptotagmin‐1 and synaptotagmin‐2 – are the main calcium sensors for fast exocytosis triggering in many cell types. Their functions extend beyond fusion triggering itself, having been implicated in the calcium‐dependent vesicle recruitment during activity, docking of vesicles to the plasma membrane and priming, and even in post‐fusion steps, such as fusion pore expansion and endocytosis. Furthermore, synaptotagmin diversity imparts distinct properties to the release process itself. Other calcium‐sensing proteins such as Munc13s and protein kinase C play important, but more indirect roles in calcium‐triggered exocytosis. Because of their higher affinity, but intrinsic slower kinetics, they operate on longer temporal and spatial scales to organize assembly of the release machinery. Finally, the high‐affinity synaptotagmin‐7 and Doc2 (Double C2‐domain) proteins are able to trigger membrane fusion in vitro, but cellular measurements in different systems show that they may participate in either fusion or vesicle priming. Here, we summarize the properties and possible interplay of (some of) the major C2‐domain containing calcium sensors in calcium‐triggered exocytosis. This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”. C2‐domain containing calcium sensors are involved in releasing the vesicular content in secretory cells. Some sensors with a low calcium affinity and fast kinetics are optimally suited for triggering the release itself, whereas others work in the priming of vesicles. The interplay of several kinds of sensors give rise to the complex release kinetics found in secretory cells. This article is part of a mini review series: “Synaptic Function and Dysfunction in Brain Diseases”.