The endothelium is a highly active organ responsible for vasculatory tone and structure, angiogenesis, as well as hemodynamic, humoral, and inflammatory responses. The endothelium is constantly exposed to blood flow, sheer stress and tension. Endothelial cells are present as a vasculature in every tissue of the body and react to and control its microenvironment. A variety of ion channels are present in the plasma membranes of endothelial cells. These include potassium channels such as inwardly rectifying potassium (K(ir)) channels, voltage-dependent (K(v)) channels, ATP-regulated potassium (K(ATP)) channels and three types of calcium-activated potassium channels (K(Ca)), the large (BK(Ca)), intermediate (IK(Ca)), and small (SK(Ca)) -conductance potassium channels. Potassium current plays a critical role in action potentials in excitable cells, in setting the resting membrane potential, and in regulating neurotransmitter release. Mitochondrial isoforms of potassium channel contribute to the cytoprotection of endothelial cells. Prominent among potassium channels are families of calcium-activated potassium channels, and especially large-conductance calcium-activated potassium channels. The modulation of BK(Ca) channels, which are voltage- and calcium-dependent, has been intensively studied. The BK(Ca) channels show large expression dynamics in endothelial cells and tissue-specific expression of large numbers of alternatively spliced isoforms. In this review, a few examples of the modulatory mechanisms and physiological consequences of the expression of BK(Ca) channels are discussed in relation to potential targets for pharmacological intervention.