The following evidence suggests that diabetes mellitus may not be the simple consequence of relative or absolute insulin deficiency by itself, but may require the presence of glucagon: (1) relative or absolute hyperglucagonæmia has been identified in every form of endogenous hyperglycæmia, including total pancreatectomy in dogs; (2) insulin lack in the absence of glucagon does not cause endogenous hyperglycæmia, but when endogenous or exogenous glucagon is present, it quickly appears, irrespective of insulin levels at the time. These facts are compatible with a bihormonal-abnormality hypothesis, which holds that the major consequence of absolute or relative insulin lack is glucose under-utilisation and that absolute or relative glucagon excess is the principal factor in the over-production of glucose in diabetes.