The release of large dense core vesicles (LDCV) by neuroendocrine cells displays a very similar calcium dependence as found in synapses, yet, the organization of channels and vesicles is quite different. Various biophysical properties of the release process, notably a large delay (>10 ms) between excitation and release and a high impact of mobile calcium buffers, suggest that, generally, vesicles and channels do not co-localize as in synapses, but are separated by a distance of 100-300 nm. This review focuses on the consequences of this organization for the functional coupling of calcium channels to LDCV-release in neuroendocrine cells. The large distance between LDCV and calcium channels in neuroendocrine cells obviates molecular interactions between channels and fusion peptides and implies that each type of calcium channel may be involved in release. Thus, preferential functional coupling of specific calcium channel types to the exocytotic process may be completely lacking, as in melanotropes. Alternatively, it may be present to some extent to induce differences in coupling efficacy between channel types, as in calf chromaffin cells and mouse pancreatic beta-cells. Physiological mechanisms, like recruitment of channels through facilitation processes or suppression of channels through inactivation, may change coupling characteristics during activity. Due to the large distance between channels and vesicles, single action potentials (APs) are usually insufficient to elicit release, and the coupling between individual APs and release is loose. Most neuroendocrine cells are therefore seen to fire in bursts, like pancreatic beta-cells. Furthermore, a large variation in shape and duration of the APs, with APs of up to 300 ms as in melanotropes, acts as another mechanism to enhance stimulus secretion coupling.