Physiological selection between different modes of cell function is based on the segregation of Ca2+ transients in different locations of the cytoplasm. Evidence in the literature suggests that in smooth muscle such segregation is effected by a large variety of specialized SR-organelle nano-junctions, each controlling the [Ca2+] in a nano-space near Ca2+ sensitive enzymes, channels, pumps and exchangers (Pan-Junctional SR). If different parts of the Pan-Junctional SR generate different localized [Ca2+], then it is likely that the SR itself is compartmentalized. However, it has been shown that the SR luminal Ca2+ concentration can be independently regulated via PM-SR junctions and that there is structural continuity throughout the SR and nuclear envelope. The answer to this paradox could be resolved by assuming that the SR lumen is irregular, has spatially separated clusters of sarco/endoplasmic reticulum Ca2+ ATPases (SERCA), inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR) and exhibits areas of restricted diffusion. Therefore, the nanospaces bordering both surfaces of the SR are critical in defining the specificity of the Ca2+ signals. In this presentation, we propose that the typical make-up of the Pan-junctional SR determines the smooth muscle type and pose the question of how to formulate a quantitatively testable hypothesis describing Ca2+ transport mechanism in junctions between the membranes of the SR and other organelles, including the plasma-membrane (PM). All vascular smooth muscles respond to physiological stimulation with Ca2+ oscillations, but three different types of Ca2+ oscillations have been reported for various blood vessels: 1. Waves of Ca2+ induced Ca2+ release (CICR) involving IP3R initiated by elevation of IP3. 2. Waves of CICR involving RyR, initiated by nicotinic acid adenine dinucleotide phosphate (NAADP)-mediated lysosomal Ca2+ release. 3. Non wave-like Ca2+ oscillations paced by periodic SR Ca2+ release. Since Ca2+ release channels exhibit Ca2+ sensitivity on both their cytoplasmic and luminal terminals, fluctuations in regional luminal Ca2+ can also function as pacemakers to determine the frequency of SR Ca2+ release waves and that of non-wave-like Ca2+ oscillations. How do we test these provocative hypotheses? At present, specific hypotheses borne out of experimental observations often yield only cartoon models and can hardly be verified by conventional experimental methods. We argue that realistic quantitative modeling of the stochastic processes characterizing ion transport in the junctions is a necessary tool on the one hand for testing of such hypothesis and on the other to generate further testable predictions on SR junction mechanisms. We briefly overview a quantitative modeling approach that integrates the available experimental evidence into a realistic reproduction of two specific vascular smooth muscle SR junctions: (1) the PM-SR junction, which appears to be at the base of CICR wave phenomena originating from IP3R Ca2+ release from the SR upon adrenergic stimulation; (2) the lysosome-SR junction, in which NAADP-mediated Ca2+ release from two pore segment channels type 2 (TPC2) seems to originate Ca2+ bursts, which cause cell-wide CICR at RyR. Finally, we address the general question of how this approach could further our understanding of the coordinated regulation of such diverse processes as vaso-motor tone, metabolism and nuclear transcription.