The great majority of the sustained secretory response of adrenal chromaffin cells to histamine is due to extracellular Ca(2+) influx through voltage-operated Ca(2+) channels (VOCCs). This is likely to be true also for other G protein-coupled receptor (GPCR) agonists that evoke catecholamine secretion from these cells. However, the mechanism by which these GPCRs activate VOCCs is not yet clear. A substantial amount of data have established that histamine acts on H(1) receptors to activate phospholipase C via a Pertussis toxin-resistant G protein, causing the production of inositol 1,4,5-trisphosphate and the mobilisation of store Ca(2+); however, the molecular events that lead to the activation of the VOCCs remain undefined. This review will summarise the known actions of histamine on cellular signalling pathways in adrenal chromaffin cells and relate them to the activation of extracellular Ca(2+) influx through voltage-operated channels, which evokes catecholamine secretion. These actions provide insight into how other GPCRs might activate Ca(2+) influx in many excitable and non-excitable cells.