Regulation of blood glucose concentrations requires an adequate number of β‐cells that respond appropriately to blood glucose levels. β‐Cell mass cannot yet be measured in humans in vivo, necessitating autopsy studies, although both pre‐ and postmorbid changes may confound this approach. Autopsy studies report deficits in β‐cell mass ranging from 0 to 65% in type 2 diabetes (T2DM), and ∼70–100% in type 1 diabetes (T1DM), and, when evaluated, increased β‐cell apoptosis in both T1DM and T2DM. A deficit of β‐cell mass of ∼50% in animal studies leads to impaired insulin secretion (when evaluated directly in the portal vein) and induction of insulin resistance. We postulate three phases for diabetes progression. Phase 1: selective β‐cell cytotoxicity (autoimmune in T1DM, unknown in T2DM) leading to impaired β‐cell function and gradual loss of β‐cell mass through apoptosis. Phase 2: decompensation of glucose control when the pattern of portal vein insulin secretion is sufficiently impaired to cause hepatic insulin resistance. Phase 3: adverse consequences of glucose toxicity accelerate β‐cell dysfunction and insulin resistance. The relative contribution of β‐cell loss versus β‐cell dysfunction to diabetes onset remains an area of controversy. However, because cytotoxicity sufficient to induce β‐cell apoptosis predictably disturbs β‐cell function, it is naïve to attempt to distinguish the relative contributions of these linked processes to diabetes onset.