Calcium regulates a wide spectrum of physiological processes such as heartbeat, muscle contraction, neuronal communication, hormone release, cell division, and gene transcription. Major entryways for Ca²⁺ in excitable cells are high-voltage activated (HVA) Ca²⁺ channels. These are plasma membrane proteins composed of several subunits, including α₁, α₂δ, β, and γ. Although the principal α₁ subunit (Ca_vα₁) contains the channel pore, gating machinery and most drug binding sites, the cytosolic auxiliary β subunit (Ca_vβ) plays an essential role in regulating the surface expression and gating properties of HVA Ca²⁺ channels. Ca_vβ is also crucial for the modulation of HVA Ca²⁺ channels by G proteins, kinases, and the Ras-related RGK GTPases. New proteins have emerged in recent years that modulate HVA Ca²⁺ channels by binding to Ca_vβ. There are also indications that Ca_vβ may carry out Ca²⁺ channel-independent functions, including directly regulating gene transcription. All four subtypes of Ca_vβ, encoded by different genes, have a modular organization, consisting of three variable regions, a conserved guanylate kinase (GK) domain, and a conserved Src-homology 3 (SH3) domain, placing them into the membrane-associated guanylate kinase (MAGUK) protein family. Crystal structures of Ca_vβs reveal how they interact with Ca_vα₁, open new research avenues, and prompt new inquiries. In this article, we review the structure and various biological functions of Ca_vβ, with both a historical perspective as well as an emphasis on recent advances.