Voltage-gated Ca2+ channels are multi-subunit complexes involved in many key functions of excitable cells. A multitude of studies in heterologous cells demonstrated that coexpression of the pore-forming α1 subunits with auxiliary α2δ and β subunits promotes membrane expression and modulates the biophysical channel properties. New null-mutant animal models and shRNA based knockdown experiments in skeletal muscle cells for the first time demonstrated the physiological roles and possible pathological effects of the α2δ-1 and β1a subunits in a differentiated excitable cell. The α2δ-1 subunit is the determinant of the typical current properties of skeletal and cardiac muscle Ca2+ channels. The β1a subunit links the skeletal muscle Ca2+ channel to the Ca2+ release channel in the sarcoplasmic reticulum. Whether these specific functions in muscle indicate similar roles of α2δ and β subunits as functional modulator and structural organizer, respectively, in neurons is being discussed.