Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg, TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors. Mutations in these transcription factors (eg, CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly, this aberrant epigenetic repression can be redressed clinically by depleting DNA methyltransferase 1 (DNMT1, a central component of the epigenetic network that mediates transcription repression) using the deoxycytidine analogue decitabine at non-cytotoxic concentrations. The DNMT1 depletion is sufficient to trigger upregulation of late-differentiation genes and irreversible cell cycle exit by p53-independent differentiation mechanisms. Fortuitously, the same treatment maintains or increases self-renewal of normal hematopoietic stem cells, which do not express high levels of lineage-specifying transcription factors. The biological rationale for this approach to therapy appears to apply to cancers other than MDS/AML also. Decitabine or 5-azacytidine dose and schedule can be rationalized to emphasize this mechanism of action, as an alternative or complement to conventional apoptosis-based oncotherapy.