Whereas deletions involving the long arm of chromosome 5 are among the most common chromosomal abnormalities in myelodysplastic syndrome (MDS), isolated del(5q) MDS, which includes the 5q- syndrome, is rare and characterized by hypoplastic anemia and a moderate risk of transformation to acute myeloid leukemia (AML). The 5q- syndrome is now recognized as a ribosomopathy, and both the classic 5q- syndrome and del(5q) MDS are uniquely responsive to lenalidomide. However, the mechanism of action of lenalidomide is controversial and involves modulation of p53 activity, which may be beneficial in anemia remission but suggested to lead to malignant cell outgrowth. Here, we critically review the literature on this important controversy, which has obvious implications for therapy of del (5q) MDS.