WENTY-FIVE YEARS AGO, William Dameshek, T the founder of this journal and one of the most creative minds in American hematology, raised a provocative question: what do aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria (PNH), and acute leukemia have in common?’His question was prompted by three observations:(1) the frequency of development of PNH in his own patients with AA,(2) the overlap between the syndromes of aplasia and PNH; and (3) the similar high prevalence of both AA and PNH in the Orient. Dameshek speculated that PNH erythropoiesis was “ecologically advantageous,” and, furthermore, that both AA and PNH might represent different responses to marrow insults (of which he listed chemicals, ionizing radiation, and viruses). In the intervening decades since Dameshek’s editorial, the prospect of survival for patients with AA has been greatly improved; we have a much better understanding of the pathophysiology of AA at the cellular level, of PNH biochemically, and of the myelodysplasia syndromes genetically. Hematopoietic cell clonality can be measured in clinical specimens and after sophisticated manipulations in animal experiments. Provisional solutions to Dameshek’s riddle may be suggested, with some temerity, in light of these new data.