The myelodysplastic syndromes (MDS) constitute a profoundly heterogeneous myeloid malignancy with a common origin in the hemopoietic stem cell compartment. Consequently, patient management and treatment are as heterogeneous. Decision-making includes identifying risk, symptoms, and options for the individual patient and to make a risk-benefit analysis. The only potential cure is allogeneic stem cell transplantation and albeit the fraction of transplanted MDS patients increase over time due to a better management and increased donor availability a majority are not eligible for this intervention. Current challenges encompass to decrease the relapse risk, the main cause of HSCT failure. Hypomethylating agents (HMA) constitute first-line treatment for higher-risk MDS. Combinations with other drugs as first-line treatment has to date not proven more efficacious than monotherapy, although combinations approved for acute myeloid leukemia, including venetoclax currently are under evaluation and often used as rescue treatment. The treatment goal for lower-risk MDS is to improve cytopenia, mainly anemia, quality-of-life, and possibly overall survival. Erythropoiesis-stimulating agents (ESAs) constitute first-line treatment for anemia and have better and more durable responses if initiated before the onset of a permanent transfusion need. Treatment in case of ESA failure or ineligibility should be tailored to the main disease mechanism; immunosuppression for hypoplastic MDS without high-risk genetics, lenalidomide for low-risk del(5q) MDS, and luspatercept for MDS with ring sideroblasts. Approved therapeutic options are still more scarce for MDS than for most other hematological malignancies. Better tools to match disease biology with treatment, i.e. applied precision medicine is needed to improve patient outcome.