Long-term, simultaneous, measurements of cytoplasmic free Ca^{2 +} concentrations and single exocytotic fusion events in surfactant-secreting type II cells were performed. All fusion (constitutive, phorbol ester-induced, and agonist-induced) was Ca^{2 +}-dependent. Kinetic analysis revealed that agonist (adenosine triphosphate [ATP])-induced fusion exhibited a kinetic pattern that correlated well with the Ca^{2 +} signal. The effects of Ca^{2 +} release from intracellular stores (early) and Ca^{2 +} entry (late) could be demonstrated for the first time by dissecting the slow (10-to-15-min) fusion response to ATP into these two components. Bath Ba^{2 +} or Sr^{2 +} could replace Ca^{2 +} to elicit a fusion response in thapsigargin-pretreated cells lacking ATP-induced Ca^{2 +} release from stores. Although the late response was partially inhibited by interrupting the phospholipase D–protein kinase C axis, a high Ca^{2 +} dependence of the entire secretory course was demonstrated by a significant correlation between the integrated Ca^{2 +} signal and the fusion response. There was also a highly significant correlation between constitutive and ATP-stimulated fusion activity in individual cells. We propose a common mechanistic model for all types of fusion in this slow secretory cell, in which constitutive and regulated forms of exocytosis are subject to the same principles of regulation.