In pancreatic acinar cells, low, threshold concentrations of acetylcholine (ACh) or cholecystokinin (CCK) induce repetitive local cytosolic Ca 2+ spikes in the apical pole, while higher concentrations elicit global signals. We have investigated the process that transforms local Ca 2+ spikes to global Ca 2+ transients, focusing on the interactions of multiple intracellular messengers. ACh‐elicited local Ca 2+ spikes were transformed into a global sustained Ca 2+ response by cyclic ADP‐ribose (cADPR) or nicotinic acid adenine dinucleotide phosphate (NAADP), whereas inositol 1, 4, 5‐trisphosphate (IP 3) had a much weaker effect. In contrast, the response elicited by a low CCK concentration was strongly potentiated by IP 3, whereas cADPR and NAADP had little effect. Experiments with messenger mixtures revealed a local interaction between IP 3 and NAADP and a stronger global potentiating interaction between cADPR and NAADP. NAADP strongly amplified the local Ca 2+ release evoked by a cADPR/IP 3 mixture eliciting a vigorous global Ca 2+ response. Different combinations of Ca 2+ releasing messengers can shape the spatio‐temporal patterns of cytosolic Ca 2+ signals. NAADP and cADPR are emerging as key messengers in the globalization of Ca 2+ signals.