Myelodysplastic syndromes (MDS) is a heterogeneous group of diseases characterized by an indolent or aggressive course based on age, blood and blast counts and aberrant cytogenetics, within a background of characteristic molecular alterations. While supportive treatment is the mainstay approach for patients with low-risk disease, hypomethylating agents are now the first-line treatment for patients with higher-risk MDS, often used as a bridge to allogeneic hematopoietic stem cell transplantation (HSCT), which remains the only curative option only for about 40-50% of patients. However, considering HSCT-related morbidity and mortality risks it is a suitable therapeutic option only for younger patients (generally up to 70 years of age) without significant comorbidities, and since the prognosis of patients who lose response or progress while on hypomethylating agents is extremely poor alternative strategies are needed. We discuss how to improve current prognostic models like IPSS and IPSS-R by integrating newer somatic mutations and discuss new epigenetic modulators being evaluated as promising new treatment of patients with MDS. Additionally, in order to reduce relapse rate and treatment related morbidity and mortality, we will discuss a newer interesting approach under pre-clinical investigation consisting of chimeric antigen receptor (CAR) modified T-cells redirected against myeloid antigens, as preparatory conditioning to an allogeneic HSCT for MDS and/or acute myeloid leukemia (AML). Newer gene modification strategies are available potentially enabling the specific targeting of myeloid blasts whilst sparing normal hematopoietic cells, with the goal of extending CAR T-cell therapies also to HSCTineligible patients, and they warrant investigations in MDS.