The myelodysplastic/preleukemic syndromes represent unique clinical situations since patients with initially mild hemopoietic abnormalities can be singled out from those progressing into frank myeloid leukemia. Here we confront data focused on the identification of critical cellular, molecular biological, cytogenetic and physiological defects leading to leukemic progression. An increasing amount of data supports our earlier hypothesis according to which the impairment of an endogenous (intracellular) life-cycle suppressor gene-product, or functionally related regulatory genes, plays the decisive role in the course of disease progression. The identification of systemic as well as clonally transmissible defects have clinical importance since in some cases the therapeutic application of the appropriate physiological substances may result in long lasting hematological remission.