In the current era of advanced supportive care and administration of recombinant cytokines and other effective therapies, patients with congenital (inherited) marrow failure syndromes usually survive the early years of life and beyond. With the extended lifespan, a new "natural history" for these syndromes is evident. Although these disorders were always classified as "benign" historically, it is now evident that most of these conditions confer an inordinately high predisposition to myelodysplastic syndromes and acute myelogenous leukemia (MDS/AML). Since carcinogenesis occurs as a sequence of events that is driven by genetic damage and by epigenetic changes, the hypothesis is advanced that the first "hit" or leukemia-initiating step is the constitutional genetic mutation, itself, that initially manifests as a single lineage or multiple lineage marrow failure. The leukemic promotion and progression steps leading to MDS/AML can then ensue readily in the initiated pool of progenitors or stem cells. Thus, the distinction between benign and malignant hematology in the context of the inherited marrow failure disorders has become blurred and new definitions for these syndromes should be developed.