AbstractCalcium (Ca²⁺) homeostasis is fundamental for cell metabolism, proliferation, differentiation, and cell death. Elevation in intracellular Ca²⁺concentration is dependent either on Ca²⁺influx from the extracellular space through the plasma membrane, or on Ca²⁺release from intracellular Ca²⁺stores, such as the endoplasmic/sarcoplasmic reticulum (ER/SR). Mitochondria are also major components of calcium signalling, capable of modulating both the amplitude and the spatio-temporal patterns of Ca²⁺signals. Recent studies revealed zones of close contact between the ER and mitochondria called MAMs (Mitochondria Associated Membranes) crucial for a correct communication between the two organelles, including the selective transmission of physiological and pathological Ca²⁺signals from the ER to mitochondria. In this review, we summarize the most up-to-date findings on the modulation of intracellular Ca²⁺release and Ca²⁺uptake mechanisms. We also explore the tight interplay between ER- and mitochondria-mediated Ca²⁺signalling, covering the structural and molecular properties of the zones of close contact between these two networks.