Angiogenesis has been shown to play a pivotal role in the growth and metastasis of solid tumors. Numerous in vitro and translational research studies have implicated a role for angiogenesis in the pathogenesis of myelodysplastic syndrome (MDS). Although the role of angiogenesis inhibitors in the treatment of solid tumors has evolved significantly over the past 5 years, their role in the treatment of hematologic malignancies such as MDS remains investigational. MDS treatment historically has been challenging, but the US Food and Drug Administration in the past 4 years has approved the hypomethylating agents 5-azacitidine and decitabine and the immunomodulatory agent lenalidomide for the 5q-syndrome. These approvals highlight recent successes in identifying and targeting pathobiologic abnormalities that contribute to MDS. Drugs such as lenalidomide and the first-generation analogue from which it was derived, thalidomide, exert multiple mechanisms of action but partially act via inhibition of angiogenesis. Over the next 5 to 10 years, preclinical and clinical evaluation of agents with more strictly defined antiangiogenic activity, such as inhibitors of vascular endothelial growth factor, or agents with partial antiangiogenesis activity, such as multitargeted tyrosine kinase inhibitors, will ultimately help define the utility of angiogenic blockade in MDS.