Ca(2+) signals in response to receptors mediate and control countless cellular functions ranging from short-term responses such as secretion and contraction to longer-term regulation of growth, cell division and apoptosis. The spatial and temporal details of Ca(2+) signals have been resolved with great precision in many cells. Ca(2+) signals activated by phospholipase C-coupled receptors have two components: Ca(2+) release from endoplasmic reticulum (ER) stores mediated by inositol 1,4,5-trisphosphate (InsP(3)) receptors, and Ca(2+) entry from outside the cell. The latter remains largely a molecular and mechanistic mystery. The activation of "store-operated" Ca(2+) channels is believed to account for the entry of Ca(2+). However, debate now focuses on how much of a contribution emptying of stores plays to the activation of Ca(2+) entry in response to physiological activation of receptors. Here we discuss recent information and ideas on the exchange of signals between the plasma membrane (PM) and ER that results in activation of Ca(2+) entry channels following receptor stimulation and/or store emptying.