Anemia remains the most challenging clinical manifestation to treat in patients with lower-risk myelodysplastic syndromes (MDS). Erythropoiesis-stimulating agents are widely used to treat anemia in such patients, but less than one third respond to these agents, and the duration of response is often limited. Lenalidomide, a second-generation immunomodulatory drug (IMiD), is approved by the US Food and Drug Administration for treatment of transfusion-dependent anemia in lower-risk MDS patients with deletion 5q chromosomal abnormality. Lenalidomide also has meaningful clinical activity in lower-risk patients without deletion 5q. The experience with lenalidomide in MDS is a modern example of reciprocal translational research, in which bench work led to an approved drug for patients, and clinical observations led to better understanding of the mechanism of action of the drug itself and even more understanding of the biology of the underlying disease. This article reviews the clinical experience with lenalidomide, highlighting recent understanding of the dual karyotype-dependent mechanisms of action.