Iatrogenic hypoglycemia, typically the result of the interplay of therapeutic hyperinsulinemia and compromised defenses resulting in hypoglycemia-associated autonomic failure (HAAF) in diabetes, is a problem for people with type 1 diabetes mellitus (T1DM). It causes recurrent morbidity is sometimes fatal, leads to recurrent hypoglycemia, and precludes euglycemia over a lifetime of T1DM. Risk factors include those that result in relative or absolute insulin excess and those indicative of HAAF in diabetes. Elimination of hypoglycemia from the lives of people with T1DM will likely be accomplished by new treatment methods that provide plasma glucose-regulated insulin replacement or secretion.