Many cellular functions of the vascular endothelium are regulated by fine-tuned global and local, microdomain-confined changes of cytosolic free Ca ([Ca]). Vasoactive agonist-induced stimulation of vascular endothelial cells (VECs) typically induces Ca release through IP receptor Ca release channels embedded in the membrane of the endoplasmic reticulum (ER) Ca store, followed by Ca entry from the extracellular space elicited by Ca store depletion and referred to as capacitative or store-operated Ca entry (SOCE). In vascular endothelial cells, SOCE is graded with the degree of store depletion and controlled locally in the subcellular microdomain where depletion occurs. SOCE provides distinct Ca signals that selectively control specific endothelial functions: in calf pulmonary artery endothelial cells, the SOCE Ca signal drives nitric oxide (an endothelium-derived relaxing factor of the vascular smooth muscle) production and controls activation and nuclear translocation of the transcription factor NFAT. Both cellular events are not affected by Ca signals of comparable magnitude arising directly from Ca release from intracellular stores, clearly indicating that SOCE regulates specific Ca-dependent cellular tasks by a unique and exclusive mechanism. This review discusses the mechanisms of intracellular Ca regulation in vascular endothelial cells and the role of store-operated Ca entry for endothelium-dependent smooth muscle relaxation and nitric oxide signaling, endothelial oxidative stress response, and excitation-transcription coupling in the vascular endothelium.