<p>Large conductance voltage- and Ca²⁺-activated K⁺ (BK) channels are key regulators of membrane excitability and intracellular Ca²⁺ signaling in a wide range of excitable and non-excitable cells. Although the biophysical properties of BK channels have been extensively characterized, it has become increasingly clear that their functional diversity arises largely from interactions with a broad network of associated proteins. In this focused review, we provide an updated overview of the BK channel protein interactome, highlighting how these interactions shape channel gating, trafficking, localization, and coupling to Ca²⁺ sources. We discuss well-established regulatory partners, including β and γ auxiliary subunits, as well as emerging modulators such as BKIP-1 and LINGO-1. We further examine interactions with cytoskeletal and trafficking proteins that govern BK channel surface expression and mobility, and with Ca²⁺-permeable channels and receptors, including voltage-gated Ca²⁺ channels, TRP channels, ryanodine receptors, IP₃ receptors, and NMDA receptors, that create specialized Ca²⁺ signaling nanodomains. Finally, we summarize the roles of intracellular signaling molecules and scaffolding proteins that integrate BK channels into larger signaling assemblies. Together, these findings position BK channels as central hubs within multiprotein complexes that enable precise, context-dependent control of cellular excitability and Ca²⁺-dependent physiological processes.</p>