Mammalian beta-cells are acutely and chronically regulated by sensing surrounding glucose levels that determine the rate at which insulin is secreted, to maintain euglycemia. Experimental research in vitro and in vivo has shown that when these cells are exposed to adverse conditions like long periods of hypoglycemia or hyperglycemia, their capability to sense glucose is decreased. Understanding the normal physiology and identifying the main players along this route becomes paramount. In this review we have taken the task to look at the role that ion channels play in the regulation of this process, delineate the different families and describe the signaling that parallels the glucose sensing process that results in insulin release.