Extracellular stimuli evoke the synthesis of intracellular second messengers, several of which couple to the release of Ca²⁺ from Ca²⁺-storing organelles via activation of cognate organellar Ca²⁺-channel complexes. The archetype is the inositol 1,4,5-trisphosphate (IP₃) and IP₃ receptor (IP₃R) on the endoplasmic reticulum (ER). A less understood, parallel Ca²⁺ signalling cascade is that involving the messenger nicotinic acid adenine dinucleotide phosphate (NAADP) that couples to Ca²⁺ release from acidic Ca²⁺ stores [e.g. endo-lysosomes, secretory vesicles, lysosome-related organelles (LROs)]. NAADP-induced Ca²⁺ release absolutely requires organellar TPCs (two-pore channels). This review discusses how ER and acidic Ca²⁺ stores physically and functionally interact to generate and shape global and local Ca²⁺ signals, with particular emphasis on the two-way dialogue between these two organelles.