Our perspective is that the concepts of glucose toxicity and glucose desensitization should be differentiated because they carry very different connotations. The term glucose desensitization most properly refers to a pharmacological event involving a temporary, readily induced, physiological and reversible state of cellular refractoriness because of repeated or prolonged exposure to high concentrations of glucose. The term glucose toxicity should be reserved for nonphysiological, irreversible alterations in cellular function caused by chronic exposure to high glucose concentrations. With regard to the pancreatic islet β-cell, the mechanism of action for glucose desensitization seems most likely to be expressed at the level of the insulin exocytotic apparatus or insulin stores within the β-cell, whereas the mechanism of action for glucose toxicity may be at the level of insulin gene transcription. This differentiation raises the possibility that exposure of patients to chronic hyperglycemia may cause glucose toxic effects on the process of insulin gene transcription and/or expression that are irreversible. If so, this may contribute to so-called secondary drug failure and, in any event, reemphasizes the need to intensify therapeutic efforts to better regulate glycemia in type II diabetes.