Autoimmune β-cell destruction occurred in otherwise diabetes-resistant F1 mice from an outcross between the nonobese diabetic (NOD) and nonobese normal (NON) inbred strains after adoptive transfer of hematopoietic stem cells from NOD donors. F1 mice were lethally irradiated and reconstituted with either NOD, NON, or F1 bone marrow. Only F1 mice reconstituted with NOD bone marrow developed hyperglycemia. The long (≥ 16-wk) prodromal period required for expression of overt diabetes contrasted with the rapidity (4–6 days) with which kidney-grafted F1 or NON islets (but not anterior pituitary) were eliminated from diabetic F1 mice. Thus, development of β-cell-specific immunologic effectors was a chronic process, but once sufficient levels of autoimmunity were achieved, implanted β-cells could be eliminated in an acute fashion. Thus, expression of NOD diabetogenic alleles in hematopoietic progenitor cells is sufficient for development of anti-β-cell immunity. The elimination of grafted NON islets shows the effectors are capable of eliminating β-cells from mice without the diabetogenic genotype.