The three SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) proteins, syntaxin, SNAP25 (synaptosome-associated protein of 25 kDa) and synaptobrevin, constitute the minimal machinery for exocytosis in secretory cells such as neurons and neuroendocrine cells by forming a series of complexes prior to and during vesicle fusion. It was subsequently found that these SNARE proteins not only participate in vesicle fusion, but also tether with voltage-dependent Ca²⁺ channels (VDCC) to form an excitosome that precisely regulates calcium entry at the site of exocytosis. In pancreatic islet -cells, ATP-sensitive K⁺ (K_ATP) channel closure by high ATP concentration leads to membrane depolarization, VDCC opening and insulin secretion, whereas subsequent opening of voltage-gated K⁺ (Kv) channels repolarizes the cell to terminate exocytosis. We have obtained evidence that syntaxin-1A (Syn-1A) physically interacts with Kv2.1 (the predominant Kv in -cells) and the sulfonylurea receptor subunit of -cell K_ATP channel to modify their gating behaviors. A model has proposed that the conformational changes of Syn-1A during exocytosis induce distinct functional modulations of K_ATP and Kv2.1 channels in a manner that optimally regulates cell excitability and insulin secretion. Other proteins involved in exocytosis, such as Munc-13, tomosyn, rab3a-interacting molecule (RIM), and guanyl nucleotide exchange factor II (GEFII), have also been implicated in direct or indirect regulation of -cell ion channel activities and excitability. This review discusses this interesting aspect that exocytotic proteins not only promote secretion per se, but also fine-tune -cell excitability via modulation of ion channel gating.