The endoplasmic reticulum (ER) lumen stores a crucial source of calcium (Ca2+) maintained orders of magnitude higher than the cytosol for the activation of a plethora of cellular responses transmitted in health and disease by a mutually efficient and communicative exchange of Ca2+ between compartments. A coordination of the Ca2+ signal is evident in the development of Ca2+ release-activated Ca2+ (CRAC) entry, vital to lymphocyte activation and replenishing of the ER Ca2+ stores, where modest decreases in ER luminal Ca2+ induce sustained increases in cytosolic Ca2+ sourced from steadfast extracellular Ca2+ supplies. While protein sensors that transduce Ca2+ signals in the cytosol such as calmodulin are succinctly understood, comparative data on the ER luminal Ca2+ sensors is only recently coming to light with the discovery that stromal interaction molecules (STIMs) sense variations in ER stored Ca2+ levels in the functional regulation of plasma membrane Orai proteins, the major component of CRAC channel pores. Drawing from data on the role of STIMs in the modulation of CRAC entry, this review illustrates the structural features that delimit the functional characteristics of ER Ca2+ sensors relative to well known cytoplasmic Ca2+ sensors.