In this review, we examine what is known about the mechanism of action of the auxiliary α₂δ subunits of voltage-gated Ca²⁺ (Ca_v) channels. First, to provide some background on the α₂δ proteins, we discuss the genes encoding these channels, in addition to the topology and predicted structure of the α₂δ subunits. We then describe the effects of α₂δ subunits on the biophysical properties of Ca_v channels and their physiological function. All α₂δ subunits increase the density at the plasma membrane of Ca²⁺ channels activated by high voltage, and we discuss what is known about the mechanism underlying this trafficking. Finally, we consider the link between α₂δ subunits and disease, both in terms of spontaneous and engineered mouse mutants that show cerebellar ataxia and spike-wave epilepsy, and in terms of neuropathic pain and the mechanism of action of the gabapentinoid drugs – small-molecule ligands of the α₂δ-1 and α₂δ-2 subunits.