The calcium ion (Ca2+) is a fundamental intracellular messenger involved in the transduction of diverse receptor signaling pathways. Transient increases in cytoplasmic Ca2+ concentration ([Ca2+]cyt) regulate many cellular functions, including the contraction of vascular smooth muscle cells (VSMCs), which are active components of the blood vessels. A key protein in intracellular Ca2+ handling is the sarco/endoplasmic reticulum (SR/ER) Ca2+ ATPase, or SERCA pump. This transmembrane protein belongs to the P-type ATPase family and uses energy from ATP hydrolysis to transport Ca2+ from the cytoplasm into intracellular reservoirs within the SR of VSMCs. By lowering [Ca2+]cyt, SERCA activity promotes vasorelaxation. In mammals, three genes, ATP2A1, ATP2A2, and ATP2A3, encode at least twelve SERCA pump isoforms. Alternative mRNA splicing is the primary mechanism for generating most isoforms, leading to tissue-specific expression patterns. In VSMCs from the aorta and mesenteric arteries, the expression of SERCA2a, SERCA2b, and, more recently, SERCA3 has been reported. This chapter will review the structure, mechanism of action, and physiological role of the SERCA pump in the intracellular Ca2+ handling of VSMCs, as well as its alterations in metabolic syndrome.