Exocytosis is an important biological process used by cells to deliver messengers or effectors to target cells with high spatial, quantitative, and kinetic precision. This process occurs by interaction and fusion of vesicles containing the (bio)chemical information with the cell membrane to release their contents into the surrounding medium. Because of its importance for life, this mechanism underlies many biological controlling factors, including different families of proteins and enzymes. Tremendous efforts have been made over the last decade toward their determination. However, in parallel, many studies have also shown that the physical and chemical characteristics of the exocytosis actors (vesicle, membrane, and extracellular medium) could directly affect the quantitative or kinetic features of secretion. The major pieces evidence for this influence, which have been reported in the literature, are reviewed herein. It demonstrates undoubtedly that pure biological aspects cannot be segregated from the physicochemical context of living mechanisms.