Recently, a refined cytogenetic and molecular classification fundamentally changed the prognostication of patients with myelodysplastic syndromes (MDS). The increasingly complex heterogeneity of this disease entity is mirrored by life expectancy rates ranging from almost a decade for very low-risk disease down to several months in higher-risk patients, even with conventional treatments. Intensive treatment approaches are hampered by the older age of most of the patients, potentially leading to an unacceptable adverse event rate. This is especially true for allogeneic hematopoietic stem cell transplantation (HCT), which, albeit of curative intent, can lead to considerable morbidity and mortality mostly as a result of organ toxicity, infectious complications, and GVHD. Furthermore, innovative drug developments, including hypomethylating agents, have broadened the therapeutic armamentarium and, although not curative, can lead to durable responses in subgroups of patients with higher-risk MDS. In fact, there is still no prospective randomized trial available that formally demonstrates the benefit of allogeneic HCT compared with standard treatments in MDS patients. In the absence of randomized data, when considering allogeneic HCT, emphasis should be put on patient selection and optimization of the pre- and posttransplantation treatment period. In these patients, a thorough comorbidity evaluation is mandatory and stratification according to age, cytogenetics, cytopenias, disease-related quality of life, and available alternative treatments should be performed in deciding whether, when, and how to perform allogeneic HCT.