Azacitidine has been approved in January 2009 in Europe in the treatment of higher-risk myelodysplastic syndromes (MDS). This represents the first time a drug is specifically labelled in MDS in Europe, and is a cornerstone in the development of hypomethylating agents 5-azacytidine (azacitidine) and 5-deoxyazacytidine (decitabine). Clinical trials of hypomethylating agents in MDS still raise a number of questions regarding the precise mode of action of these drugs, as well as the optimal sequencing of treatment in MDS. The positive results of these trials also open the field of epigenetic therapeutic strategies combining hypomethylating agents with other classes of drugs targeting epigenetic processes.