Iatrogenic hypoglycemia is the limiting factor in the glycemic management of diabetes. It can be caused by sulfonylureas or other insulin secretagogues, and perhaps by metformin, as well as by insulin. Hypoglycemia is less frequent overall in type 2 diabetes (T2DM), compared with type 1 diabetes (T1DM). However, it becomes a progressively more frequent problem, ultimately approaching that in T1DM, in advanced (i.e., insulin deficient) T2DM because of compromised glucose counterregulation – the syndromes of defective glucose counterregulation and hypoglycemia unawareness, the components of hypoglycemia-associated autonomic failure – analogous to that which develops early in the course of T1DM. Clearly, prevention of hypoglycemia is preferable to its treatment. By practicing hypoglycemia risk reduction – addressing the issue, applying the principles of aggressive glycemic therapy and considering both the conventional risk factors and those indicative of compromised glucose counterregulation – the therapeutic goal is to reduce mean glycemia as much as can be accomplished safely in a given patient at a given stage of T2DM. Particularly in view of the growing array of glucose-lowering drugs that can be used to optimize therapy, hypoglycemia should not be used as an excuse for poor glycemic control. Nonetheless, better methods, such as those that would provide plasma glucose regulated insulin secretion or replacement, are needed for people with T2DM, as well as those with T1DM, if euglycemia is to be maintained over a lifetime of diabetes.