Abstract Multiple mechanisms that maintain Ca 2+ homeostasis and provide for Ca 2+ signalling operate in the somatas and neurohypophysial nerve terminals of supraoptic nucleus (SON) neurones. Here, we examined the Ca 2+ clearance mechanisms of SON neurones from adult rats by monitoring the effects of the selective inhibition of different Ca 2+ homeostatic molecules on cytosolic Ca 2+ ([Ca 2+] i) transients in isolated SON neurones. In addition, we measured somatodendritic vasopressin (AVP) release from intact SON tissue in an attempt to correlate it with [Ca 2+] i dynamics. When bathing the cells in a Na +-free extracellular solution, thapsigargin, cyclopiazonic acid (CPA), carbonyl cyanide 3-chlorophenylhydrazone (CCCP), and the inhibitor of plasma membrane Ca 2+-ATPase (PMCA), La 3+, all significantly slowed down the recovery of depolarisation (50 mM KCl)-induced [Ca 2+] i transients. The release of AVP was stimulated by 50 mM KCl, and the decline in the peptide release was slowed by Ca 2+ transport inhibitors. In contrast to previous reports, our results show that in the fully mature adult rats: (i) all four Ca 2+ homeostatic pathways, the Na +/Ca 2+ exchanger, the endoplasmic reticulum Ca 2+ pump, the plasmalemmal Ca 2+ pump and mitochondria, are complementary in actively clearing Ca 2+ from SON neurones; (ii) somatodendritic AVP release closely correlates with intracellular [Ca 2+] i dynamics; (iii) there is (are) Ca 2+ clearance mechanism(s) distinct from the four outlined above; and (iv) Ca 2+ homeostatic systems in the somatas of SON neurones differ from those expressed in their terminals.