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Calcium is a universal second messenger that controls many cell functions including proliferation and migration which are hallmarks of proliferative disease such as vascular occlusive diseases.STIM and Orai proteins have recently emerged as the molecular correlates for the highly calcium selective conductances mediated by store-operated calcium entry (SOCE) and store-independent Arachidonate-regulated calcium (ARC) channels.Store-operated calcium entry (SOCE) is controlled by the extent of filling of the internal calcium stores, mainly the endoplasmic reticulum (ER), while ARC channels are activated downstream of arachidonate production by mechanisms that remain unclear.Vascular smooth muscle cell (VSMC) proliferation and migration is a major contributor to vascular diseases such as atherosclerosis, hypertension and restenosis.We previously showed that proliferative migratory VSMCs (called "synthetic") display up-regulated STIM and Orai proteins.Here we will describe recent findings from our group of STIM and Orai isoform-specific requirement for mediating store-dependent and store-independent calcium entry pathways in VSMCs.We will also discuss the requirement of STIM and Orai proteins in VSMC proliferation and migration in vivo using animal models of vascular diseases and will discuss the implications of these findings in the pathophysiology of these diseases.