Multiple studies have shown that hypoglycemia is associated with increased mortality and a variety of adverse outcomes. Whether hypoglycemia is a mediator of adverse outcomes or simply represents a marker of critical illness has been unclear until now. Based on observational data, spontaneous (but not iatrogenic) hypoglycemia is associated with increased mortality during hospitalization for acute myocardial infarction. In the recent ADVANCE trial of patients with diabetes, intensive glucose lowering was associated with increased risk of hypoglycemia. Hypoglycemia was, in turn, associated with increased risk of macro- and microvascular events and death, and also with increased risk of noncardiac adverse events, including disorders of the digestive, respiratory, and skin systems. Based on available evidence, hypoglycemia does not appear to directly lead to death or cardiovascular events and is likely a marker for more severe illness and comorbidity burden. Nevertheless, continued efforts to avoid hypoglycemia are clearly warranted.