Voltage-gated Ca2C channels represent one of the main pathways for Ca2C entry into nerve terminals where they play a critical role in the control of synaptic exocytosis. It is traditionally believed that the vesicle-docking/release machinery must be located in the vicinity of the calcium source in order to trigger fast, efficient and spatially delimited neurotransmitter release. This tight coupling is mostly achieved by a physical interaction of the presynaptic calcium channel with several actors of the synaptic vesicle release machinery. Conversely, the binding of synaptic proteins regulates calcium channel activity, providing for fine control of presynaptic Ca2C entry. Here, we review the current state of knowledge of the molecular mechanisms by which synaptic proteins regulates presynaptic Ca2C channel activity.