Chromaffin granules are organelles similar to the large dense cored vesicles (LDCV) found in many neurons. They accumulate catecholamines and other soluble components at concentrations that may result in a hypertonic intravesicular medium. However, they maintain isotonicity with cytosol probably as result of aggregation of intravesicular components. Chromogranins could play a role in that isotonic equilibrium as well as in the control of the free diffusion of catecholamines to the external media once granule fusion occurs. Although the release of soluble components upon exocytosis has been considered as a merely passive phenomenon, we have demonstrated that it is finely modulated by second messengers and, therefore, interfered with drugs. Our data suggest that the main regulatory target for these signals is not the fusion pore but most probably intravesicular factors like pH and chromogranins. We also present results suggesting that chromogranins are involved in the mechanisms that modulate the latter steps of exocytosis. Of importance, changes in the kinetics of exocytosis or/and in the quantal size can result in profound modifications to synaptic performance, at least in those processes mediated by LDCV.