Large-conductance, Ca²⁺-activated K⁺ (BK_Ca) channels in smooth muscle cells are unique because they integrate changes in both intracellular Ca²⁺ and membrane potential. Protein kinases such as cAMP-dependent protein kinase, cGMP-dependent protein kinase and protein kinase C can affect tissue function by ‘tuning' the apparent Ca²⁺- and/or voltage-sensitivity of the BK_Ca channel to physiological changes in both Ca²⁺ concentrations and membrane potential. However, despite the central importance of kinase-mediated modulation of BK_Ca channels in different smooth muscle tissues, many key issues, including the sites and mechanisms of actions of protein kinases, remain unresolved. In this article, the role of protein kinases in the regulation of BK_Ca channels is discussed.