Diabetes remains one of the leading causes of morbidity and mortality worldwide, affecting an estimated 422 million adults. In the U.S. it is predicted that 1 in every 3 children born as of 2000 will suffer from diabetes in their lifetime. Type 2 diabetes results from combinatorial defects in pancreatic beta cell glucose-stimulated insulin secretion and in peripheral glucose uptake. Both processes, insulin secretion and glucose uptake, are mediated by exocytosis proteins, SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) complexes, Sec1/Munc18 (SM), and Double C2-domain protein B (DOC2B). Increasing evidence links deficiencies in these exocytosis proteins to diabetes in rodents and humans. Given this, emerging studies aimed at restoring and/or enhancing cellular levels of certain exocytosis proteins point to promising outcomes in maintaining functional beta cell mass and enhancing insulin sensitivity. In doing so, new evidence also shows that enhancing exocytosis protein levels may promote health span and longevity, and may also harbor anti-cancer and anti-Alzheimer's disease capabilities. Herein we present a comprehensive review of the described capabilities of certain exocytosis proteins and how these might be targeted for improving metabolic dysregulation.