Calcium (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.