Azacitidine (Aza C), a pyrimidine nucleoside analog, was developed as an antitumor agent. In addition to cytotoxic effects, it induces differentiation of malignant cells in vitro. Aza C inhibits DNA methyltransferase, the enzyme in mammalian cells responsible for methylating newly synthesized DNA, resulting in synthesis of hypomethylated DNA and changes in gene transcription and expression. The mechanism by which Aza C produces its effects is most likely multifactorial. Aza C can produce significant myelosuppression, particularly at higher doses. Aza C could also be acting as a biologic response modifier. The response of hematopoietic progenitors to cytokines is impaired in patients with MDS. This may be attributable in part to abnormalities of the signal transduction pathway downstream from the cytokine receptors. In vitro data suggest that Aza-C can modulate the cytokine signal transduction pathway, rendering sensitive unresponsive cells to the effects of cytokines, partially restoring normal hematopoietic regulation. Incorporation of Aza-C into DNA inhibits DNA methyltransferase and induces DNA hypomethylation. 5-Azacytidine and 5-Aza-2_-deoxycytidine (decitabine), 2 potent inhibitors of cytosine methylation, have shown strong antileukemic activity in acute myeloid leukemia (AML). In addition, both induce trilineage responses in myelodysplastic syndromes (MDS) at dose levels allowing for outpatient management, with moderate myelotoxicity and no significant nonhematologic toxicity.