Myelodysplastic syndromes are a heterogeneous group of bone marrow disorders that result in cytopenias and a propensity to develop secondary leukemia. While allogeneic transplantation still remains the only potential curative treatment option, it can only be offered to a limited number of patients. For the majority, who are not transplant candidates, treatment strategies cover iron chelation, growth factors, lenalidomide, and hypomethylating agents to improve cytopenia and potentially delay disease progression. These limited options underpin the urgent need for more translational research-based clinical trials in well-defined subgroups of patients with myelodysplastic syndromes. Indeed, myelodysplastic syndromes are a moving target with maximum innovation in the understanding of the complex molecular pathways during the last decade. Compared with other hematological diseases such as myeloma, this has unfortunately not yet translated into approval of novel treatment options. Given the current developments in the field, we are optimistic that recent frustrations will be overcome shortly and this will pave the way for exciting opportunities, especially for patients not responding to first-line therapeutic options.