Several classification and scoring systems have been developed in myelodysplastic syndromes (MDS to predict the risk of progression to acute myeloid leukemia and survival. These prognostication models have been also used to inform therapeutic decision-making in a risk-adapted fashion. Patient-related factors such as age, comorbidities, and functional status have to be considered as well. Here we review a risk-guided therapeutic approach for the management of MDS patients. It is anticipated that the improved understanding of the complex pathogenesis of MDS and the recent discovery of important molecular lesions will be translated into novel therapeutic approaches. Additionally, some prognostic aberrations are expected to be incorporated into the prognostic tools with the goal of improving their prognostic precision and therefore allow for a more informed therapeutic decision-making based on the individual's risk profile.