Voltage-gated calcium channels are thought to exist in the plasma membrane as heteromeric proteins, in which the α1 subunit is associated with two auxiliary subunits, the intracellular β subunit and the α₂δ subunit; both of these subunits influence the trafficking and properties of Ca_V1 and Ca_V2 channels. The α₂δ subunits have been described as type I transmembrane proteins, because they have an N-terminal signal peptide and a C-terminal hydrophobic and potentially transmembrane region. However, because they have very short C-terminal cytoplasmic domains, we hypothesized that the α₂δ proteins might be associated with the plasma membrane through a glycosylphosphatidylinositol (GPI) anchor attached to δ rather than a transmembrane domain. Here, we provide biochemical, immunocytochemical, and mutational evidence to show that all of the α₂δ subunits studied, α₂δ-1, α₂δ-2, and α₂δ-3, show all of the properties expected of GPI-anchored proteins, both when heterologously expressed and in native tissues. They are substrates for prokaryotic phosphatidylinositol-phospholipase C (PI-PLC) and trypanosomal GPI-PLC, which release the α₂δ proteins from membranes and intact cells and expose a cross-reacting determinant epitope. PI-PLC does not affect control transmembrane or membrane-associated proteins. Furthermore, mutation of the predicted GPI-anchor sites markedly reduced plasma membrane and detergent-resistant membrane localization of α₂δ subunits. We also show that GPI anchoring of α₂δ subunits is necessary for their function to enhance calcium currents, and PI-PLC treatment only reduces calcium current density when α₂δ subunits are coexpressed. In conclusion, this study redefines our understanding of α₂δ subunits, both in terms of their role in calcium-channel function and other roles in synaptogenesis.