As one of the leading causes of morbidity and mortality worldwide, diabetes affects an estimated 422 million adults, and it is expected to continue expanding such that by 2050, 30% of the U.S. population will become diabetic within their lifetime. Out of the estimated 422 million people currently afflicted with diabetes worldwide, about 5% have type 1 diabetes (T1D), while the remaining ~95% of diabetics have type 2 diabetes (T2D). Type 1 diabetes results from the autoimmune-mediated destruction of functional β-cell mass, whereas T2D results from combinatorial defects in functional β-cell mass plus peripheral glucose uptake. Both types of diabetes are now believed to be preceded by β-cell dysfunction. T2D is increasingly associated with numerous reports of deficiencies in the exocytosis proteins that regulate insulin release from β-cells, specifically the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins. SNARE protein’s functionality is further regulated by a variety of accessory factors such as Sec1/Munc18 (SM), double C2-domain proteins (DOC2), and additional interacting proteins at the cell surface that influence the fidelity of insulin release. As new evidence emerges about the detailed mechanisms of exocytosis, new questions and controversies have come to light. This emerging information is also contributing to dialogue in the islet biology field focused on how to correct the defects in insulin exocytosis. Herein we present a balanced review of the role of exocytosis proteins in T2D, with thoughts on novel strategies to protect functional β-cell mass.