The hypomethylating agent 5-Azacytidine epigenetically modulates various genes, including tumor suppressor genes. For many years, the "new agent", which was first discovered in the 1960s, remained fairly unobtrusive in the rank of salvage treatment options for myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). When the significance of epigenetics in tumorigenesis became clear, 5-Azacytidine attracted new attention. Finally, it was the first drug approved for the treatment of all categories of MDS, and its survival benefit over best conventional care was confirmed. Today, in many clinical situations, when aggressive therapies including allogeneic hematopoietic cell transplantation are not an option, 5-Azacytidine is the first treatment of choice. Preliminary data on combinations of the hypomethylating agent with other new drugs are promising, and innovative strategies involving immune modulation and regenerative tissue repair hold a broad potential for future developments.