Myelosysplastic syndromes (MDS) include a heterogeneous group of clonal myeloid neoplasms characterized by ineffective hematopoiesis leading to blood cytopenias and a variable risk of progression into acute myeloid leukemia (AML). Although the hypomethylating agent azacitidine prolongs survival among patients with higher risk (HR)-MDS compared with conventional care, no drug has been shown conclusively to prolong survival or delay progression to AML among patients with lower-risk MDS (LR-MDS). Lenalidomide is the drug with the most impressive clinical activity in the subset of anemic LR-MDS patients who harbor a deletion of the long arm of chromosome 5 (5q-), where it leads to high rates of transfusion independence and cytogenetic responses. Furthermore, lenalidomide delays progression to AML and prolongs survival among responders. In this article, we review the recently recognized mechanisms of action of lenalidomide and discuss the most recent clinical data regarding its use in patients with both 5q- MDS as well as non-5q- MDS. Finally, we forecast the future directions to improve the efficacy of lenalidomide in MDS with and without 5q-.