In recent years, rapid discoveries have been made relating to Ca²⁺ handling at specific organelles that have important implications for whole-cell Ca²⁺ homeostasis. In particular, the structures of the endoplasmic reticulum (ER) Ca²⁺ channels revealed by electron cryomicroscopy (cryo-EM), continuous updates on the structure, regulation, and role of the mitochondrial calcium uniporter (MCU) complex, and the analysis of lysosomal Ca²⁺ signaling are milestones on the route towards a deeper comprehension of the complexity of global Ca²⁺ signaling. In this review we summarize recent discoveries on the regulation of interorganellar Ca²⁺ homeostasis and its role in pathophysiology.