The central and peripheral nervous systems express multiple types of ligand and voltage-gated calcium channels (VGCCs), each with specific physiological roles and pharmacological and electrophysiological properties. The members of the Ca(v)2 calcium channel family are located predominantly at presynaptic nerve terminals, where they are responsible for controlling evoked neurotransmitter release. The activity of these channels is subject to modulation by a number of different means, including alternate splicing, ancillary subunit associations, peptide and small organic blockers, G-protein-coupled receptors (GPCRs), protein kinases, synaptic proteins, and calcium-binding proteins. These multiple and complex modes of calcium channel regulation allow neurons to maintain the specific, physiological window of cytoplasmic calcium concentrations which is required for optimal neurotransmission and proper synaptic function. Moreover, these varying means of channel regulation provide insight into potential therapeutic targets for the treatment of pathological conditions that arise from disturbances in calcium channel signaling. Indeed, considerable efforts are presently underway to identify and develop specific presynaptic calcium channel blockers that can be used as analgesics.