Calcium influx into presynaptic nerve terminals via voltage-gated Ca2+ channels is an essential step in neurotransmitter release. The predominant Ca2+ channel species in synaptic nerve terminals are P/Q-type and N-type channels, with their relative levels of expression varying across the nervous system. The different distributions of these two channel subtypes are reflected in their distinct physiological and pathological roles, yet their activity is regulated by common mechanisms and both function as part of larger signaling complexes that enable their precise regulation and subcellular targeting. Here, we provide a broad overview of molecular and cellular mechanisms that regulate Ca2+ channels, and how these cellular signaling pathways are integrated at the level of the channel protein.