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Advances in therapy can essentially be measured using two parameters; introduction of a new agent which benefits an increased number of patients over prevailing treatments or more selective use of an existing drug by matching it to the biologic characteristics associated with response. In reviewing the therapeutic landscape of myelodysplastic syndromes (MDS), both should be applied to gauge the advances in therapy. While several new drugs are currently in clinical trials for the treatment of MDS, three drugs were approved for use in the last decade and sufficient time has elapsed to take stock of the benefit they have produced in the outcome of patients both in terms of survival and quality of life. For the two hypomethylating agents, response remains limited to 50% patients at best, and no strategy has evolved to allow for pre-selection of likely responders, however, 5-azacytidine has been associated with improvement in the survival of higher risk patients. The benefit of lenalidomide was found to be greater for del(5q) patients with transfusion dependent anemia and lower risk disease right from the start, although a quarter of the non-del(5q) patients also experienced complete transfusion independence with this agent. It is in this latter group of non-del(5q) cases that a strategy for potentially preselecting likely responders is suggested by the finding of an expression profile associated with response. In this paper, we will focus on defining our current understanding of the mechanisms of action of the existing FDA approved drugs in order to identify therapeutic strategies that are suitable for specific MDS subtypes. We expect that through advancing biologic insights, the use of such therapies will become more selective and refined., (Copyright © 2011 Elsevier Ltd. All rights reserved.)