N-type or CaV2.2 high-voltage activated calcium channels are distinguished by exclusively neuronal tissue distribution, sensitivity to ω-conotoxins, prominent inhibition by G-proteins, and a unique role in nociception. Most investigated modulatory pathway regulating the CaV2.2 channels is G-protein-coupled receptor-activated pathway leading to current inhibition by Gβγ subunit of G-protein. Binding of Gβγ dimer to α1 subunit of the CaV2.2 channel transfers the channel form "willing" to "reluctant" gating state. Channel phosphorylation by protein kinase C potentiates N-type calcium current. CaV2.2 channels could be functionally regulated also by a number of protein-protein interactions. Ca V2.2 null mice are hyposensitive to inflammatory and neuropathic pain, otherwise they have a mild phenotype. Consistent with the mild phenotype of the CaV2.2-/- mice, reports on mutations linked to a disease phenotype are scarce. Only one mutation related to human heritable diseases was identified until now. Pharmaceutical inhibition of CaV2.2 channels either by direct inhibition of the channel, by an activation of G-protein coupled receptors, or by inhibition of membrane targeting of the channel protein are promising strategies for treatment of severe chronic and/or neuropathic pain.