We measured the exocytotic response induced by a rapid and global increase in the concentration of Ca²⁺ or GTPγS (achieved by flash photolysis of caged compounds) in mast cells and chromaffin cells. Secretion was measured by following both cell membrane capacitance and amperometry. When Ca²⁺ was used to trigger secretion, we observed an immediate increase in capacitance, however, the first amperometric spike observed was delayed with respect to the change in capacitance (∼5 s in mast cells and ∼0.6 s in chromaffin cells). In contrast, when GTPγS was used to trigger secretion no such discrepancy was seen, both measurements reported a secretory response that was similarly delayed with respect to the stimulus. These data suggest that the capacitance increase, when triggered by a large Ca²⁺ step, reports events that do not result in the fusion of vesicles containing oxidizable substances. These results contrast with the smaller secretory responses evoked by the transient opening of Ca²⁺ channels. Under these more physiological conditions, pulsed-laser imaging studies revealed that the Ca²⁺ influx was localized to discrete areas at the plasma membrane. Thus the Ca²⁺ stimulus triggered by DM-nitrophen fails to reproduce the small localized changes seen during a physiological stimulation and creates an artifactual non-secretory capacitive response.