Voltage-gated calcium channels (CaV) are involved in diverse physiological functions, including synaptic neurotransmission and excitation-contraction coupling. Each CaV consists minimally of three subunits: the pore-forming α1 subunit and auxiliary β and α2/δ subunits. Although the mechanisms involved are not fully understood, both auxiliary subunits are known to modulate the activity and subcellular localisation of CaVs, and, thus, the fine-tuning of calcium signalling within cells. Recent evidence from studies, using heterologous expression systems and native cerebellar tissue, suggests that CaV-α1 and α2/δ-2 – a gabapentinoid-sensitive α2/δ isoform – are present in macromolecular signalling complexes termed lipid rafts, (Davies et al, 2006, Xia et al, 2007). However, it is unclear whether CaV-α1 raft targeting is dependent or independent of the α2/δ subunit. Using electrophysiological, biochemical and imaging approaches we now show that wild type α2/δ-1 – a gabapentinoid-sensitive homologue of α2/δ-2 – is localised in cell surface puncta both in in vitro sensory adult rat dorsal root ganglion neurons and transfected COS-7 cells. Moreover, a fully functional epitope (HA)-tagged α2/δ-1 subunit not only exhibits the punctate distribution at the cell surface but crucially, also co-localises with endogenous lipid raft proteins, caveolin and flotillin. Upon sucrose gradient fractionation of transfected COS-7 cell lysates in Triton-X-100, approximately 30% of total cellular α2/δ-1-HA migrates into the buoyant lipid raft fraction, whereas CaV2.2 α1 subunits (co-expressed with β1b only) migrate as classical non-raft proteins. However, upon co-expression with α2/δ-1, approximately 40% of total cellular CaV2.2 (+β1b) complexes now migrate into lipid rafts. Treatment of live cells (pre-lysis) with the cholesterol-depleting – lipid raft disrupting – methyl-β-cyclodextrin (MBC; 10mM, 1 h) abolishes lipid raft association of CaV2.2 (+β1b)/α2/δ-1-HA complexes (or α2/δ-1-HA alone). Furthermore, electrophysiology reveals an inhibitory effect of MBC-mediated raft disruption that is present when CaV2.2/β1b complexes are expressed with α2/δ-1-HA (~25% decrease in maximal peak current density, Imax), but not when α2/δ-1-HA is absent. Taken together, our data indicate that α2/δ-1 subunits are both necessary and sufficient for targeting CaV-α1/β complexes to plasma membrane lipid rafts. The ability of α2/δ-1 to target CaV channels into discrete membrane microdomains is likely to allow CaVs access to the plethora of raft-associated signalling proteins that are known to modulate their activity (Catterall et al, 2006). Indeed, α2/δ-mediated targeting of CaVs into lipid rafts may be a primary physiological function of gabapentinoid-sensitive, and perhaps all α2/δ subunits.