Using rat beta-cells we present evidence that Sr2+ and Ba2+, like Ca2+, support depolarization-induced increases in membrane capacitance which reflect insulin granule exocytosis. Even with identical total charge entry, Sr2+ and Ba2+ are 3-5 and 20-fold less effective than Ca2+ in supporting release. While exocytosis supported by Sr2+ is graded with cation entry and complete within 250ms of depolarization, exocytosis supported by Ba2+ begins abruptly after a threshold of charge entry and continues for many seconds. Ba(2+)-supported release continues in the presence of greatly enhanced cytosolic Ca2+ buffering, arguing against release of Ca2+ from stores as its principal action. These results suggest that Sr2+ and Ba2+ support exocytosis largely by binding to Ca(2+)-dependent release-activating sites, though with less affinity than Ca2+.