Store-operated channels (SOC) and Ca²⁺ entry (SOCE) have been described in a wide variety of vascular smooth muscle cells (SMC), and were shown to play an important role in agonist-induced constriction and nitric oxide-induced relaxation in conduit vessels. Molecular identity and mechanism of SOC activation remain highly controversial, making it hard to assess the exact role of SOCE in microvascular function. Recent advancements in the SOCE field identified Orai1 as a new molecular candidate for SOC (Feske et al. 2006; Vig et al. 2006; Yeromin et al. 2006; Luik et al. 2006b), STIM1 as an activator of the SOCE pathway (Liou et al. 2005; Mercer et al. 2006; Wu et al. 2006; Baba et al. 2006; Luik et al. 2006a; Csutora et al. 2007), and Ca²⁺-independent phospholipase A₂ beta (iPLA₂β) as a crucial component for signal transduction from the stores to the plasma membrane channels (Smani et al. 2003; Smani et al. 2004; Vanden Abeele et al. 2004; Martinez & Moreno, 2005; Singaravelu et al. 2006; Boittin et al. 2006; Csutora et al. 2006; Csutora et al. 2007). However, alternative models suggest that SOC may be encoded by TRPC1 (Beech, 2005; Liu et al. 2003; Rosado et al. 2002; Ambudkar, 2007), and instead of iPLA₂β and a diffusible messenger, conformational coupling of TRPC1 to the IP₃ receptor, STIM1, or other components of the endoplasmic reticulum may be responsible for SOCE activation (Boulay et al. 1999; Rosado & Sage, 2001; Rosado & Sage, 2000; Yuan et al. 2003; Huang et al. 2006; Lopez et al. 2006; Ong et al. 2007). In this review new experimental evidence will be presented on the crucial role of Orai1, STIM1 and iPLA₂β in SOCE mechanism and SMC function. A novel unifying model will be introduced that could account for most of the experimental evidence obtained so far by different groups of investigators that was originally used in favor of multiple mutually exclusive SOCE mechanisms. Using new knowledge and experimental tools we will address the questions on what is the role of SOC channels in Ca²⁺ entry and constriction of cerebral, mesenteric and carotid arteries, and how SOC, TRPC1 and voltage-gated L-type Ca²⁺ channels may peacefully play together, and could all be very important for SMC and microvascular function.