In a variety of cell types, calcium influx is essential for regulating a host of kinetically distinct processes including exocytosis, enzyme control, gene regulation, cell growth and proliferation and apoptosis. Although several distinct calcium entry pathways have been described, in non-excitable cells the major calcium entry pathway is the store-operated one, in which the emptying of intracellular inositol trisphosphate-sensitive calcium stores activates calcium influx (store-operated calcium entry, or capacitative calcium entry). Several biophysically distinct store-operated currents have been reported, but the best characterized is the calcium release-activated calcium current, ICRAC. Recent work has revealed a central role for mitochondria in the regulation of ICRAC, and this is particularly prominent under physiological conditions. Mitochondria take up some of the calcium that has been released from the stores by inositol trisphosphate, resulting in more extensive store depletion and hence activation of ICRAC. ICRAC is subject to calcium-dependent inactivation but this is reduced by mitochondrial calcium buffering. Hence mitochondria regulate both activation and inactivation of CRAC channels. Through effects on CRAC channel gating, mitochondria are effective regulators of both calcium-dependent exocytosis and secretion of pro-inflammatory signals like leukotrienes. ICRAC therefore represents a dynamic interplay between endoplasmic reticulum, mitochondria and plasma membrane and this interaction sculpts subsequent calcium-dependent responses.