This work offers a comprehensive approach to understanding the phenomena underlying vesicular exocytosis, a process involved in vital functions of living organisms such as neuronal and neuroendocrine signaling. The kinetics of release of most neuromediators that modulate these functions in various ways can be efficiently monitored using single-cell amperometry (SCA). Indeed, SCA at ultramicro- or nanoelectrodes provides the necessary temporal, flux, and nanoscale resolution to accurately report on the shape and intensity of single exocytotic spikes. Rather than characterizing amperometric spikes using standard descriptive parameters (e.g., amplitude and half-width), however, this study summarizes a modeling approach based on the underlying biology and physical chemistry of single exocytotic events. This approach provides deeper insights into intravesicular phenomena that control vesicular release dynamics. The ensuing model’s intrinsic parsimony makes it computationally efficient and friendly, enabling the processing of large amperometric traces to gain statistically significant insights.