Abstract  Cross‐talk between organelles and plasma membrane Ca2+ channels is essential for modulation of the cytosolic Ca2+ ([Ca2+]C) signals, but such modulation may differ among cells. In chromaffin cells Ca2+ entry through voltage‐operated channels (VOCC) induces calcium release from the endoplasmic reticulum (ER) that amplifies the signal. [Ca2+]C microdomains as high as 20–50 μM are sensed by subplasmalemmal mitochondria, which accumulate large amounts of Ca2+ through the mitochondrial Ca2+ uniporter (MCU). Mitochondria confine the high‐Ca2+ microdomains (HCMD) to beneath the plasma membrane, where exocytosis of secretory vesicles happens. Cell core [Ca2+]C is much smaller (1–2 μM). By acting as a Ca2+ sink, mitochondria stabilise the HCMD in space and time. In non‐excitable HEK293 cells, activation of store‐operated Ca2+ entry (SOCE), triggered by ER Ca2+ emptying, did also generate subplasmalemmal HCMD, but, in this case, most of the Ca2+ was taken up by the ER rather than by mitochondria. The smaller size of the [Ca2+]C peak in this case (about 2 μM) may contribute to this outcome, as the SERCA has much higher Ca2+ affinity than MCU. There is also possible that relative positioning of organelles, channels and effectors, as well as cytoskeleton and accessory proteins play an important role. This article is protected by copyright. All rights reserved.