The presence of del(5q), either as the sole karyotypic abnormality or as part of a more complex karyotype, has distinct clinical implications for myelodysplastic syndromes (MDS) and acute myeloid leukemia. The 5q- syndrome, a subtype of low-risk MDS, is characterized by an isolated 5q deletion and <5% blasts in the bone marrow and can serve as a useful model for studying the role of 5q deletions in the pathogenesis and prognosis of myeloid malignancies. Recent clinical results with lenalidomide, an oral immunomodulatory drug, have shown durable erythroid responses, including transfusion independence and complete cytogenetic remissions in patients with del(5q) MDS with or without additional chromosomal abnormalities. These results indicate that lenalidomide can overcome the pathogenic effect of 5q deletion in MDS and restore bone marrow balance. The data provide important new insights into the pathobiology of 5q chromosomal deletions in myeloid malignancies.