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The precise diagnostic tests and subsequent prognostic stratification for patients with myelodysplastic syndrome (MDS) are often cumbersome, yet they are the basis of successful therapy. Diverse treatment options are available for these patients; however, the decisions in real-life are often not grounded on the available evidence. Although the International Prognostic Scoring System and revised International Prognostic Scoring System are still driving the medical approach to MDS patients, additional variables must be considered when therapeutic intervention is needed. A rational scheme for first-line therapy is described that allows for the possibility of selecting the optimal individual therapy for MDS patients.