Ca2+ influx into excitable cells is a prerequisite for neurotransmitter release and regulated exocytosis. Within the group of ten cloned voltage-gated Ca2+ channels, the Cav2.3-containing E-type Ca2+ channels are involved in various physiological processes, such as neurotransmitter release and exocytosis together with other voltage-gated Ca2+ channels of the Cav1, Cav2 and Cav3 subfamily. However, E-type Ca2+ channels also exhibit several subunit-specific features, most of which still remain poorly understood. Cav2.3-containing R-type channels (here called ‘E-type channels’) are also located in presynaptic terminals and interact with some synaptic vesicle proteins, the so-called SNARE proteins, although lacking the classical synprint interaction site. E-type channels trigger exocytosis and are also involved in long-term potentiation. Recently, it was shown that the interaction of Cav2.3 with the EF-hand motif containing protein EFHC1 is involved in the aetiology and pathogenesis of juvenile myoclonic epilepsy.