Type 2 diabetes (T2D) has been considered a relentlessly worsening disease, due to the progressive deterioration of the pancreatic beta cell functional mass. Evidence indicates that remission of T2D may occur in variable proportions of patients after specific treatments that are associated with recovery of beta cell function. The recovery of beta cells has been shown in human islets obtained from non-diabetic organ donors that recover from “lipo-glucotoxic” conditions, and human islets isolated from T2D organ donors exposed to specific treatments or by a period of exposure to a “non-diabetic” milieu. The improvement of insulin secretion and the associated molecular traits unveil the possibility to promote T2D remission by directly targeting pancreatic beta cells.