The treatment of patients with myelodysplastic syndromes (MDS) begins with assessment of karyotype and risk. Lenalidomide is approved for the treatment of patients who have transfusion-dependent anemia due to lower-risk MDS with chromosome 5q deletion (del(5q)) with or without additional cytogenetic abnormalities, and isolated del(5q) only in the European Union. Mounting evidence suggests that lenalidomide is effective not only in reducing red blood cell (RBC) transfusion burden, but also in modifying the disease natural history by suppressing the malignant clone. Data discussed here from the pivotal phase 2 (MDS-003) and phase 3 (MDS-004) studies of lenalidomide demonstrate that lenalidomide treatment was associated with both short- and long-term benefits. These clinical benefits included high rates of RBC-transfusion independence (TI) with prolonged durations of response, high rates of cytogenetic response (CyR) associated with achievement of durable RBC-TI, no significant difference in rates of progression to acute myeloid leukemia (AML), and improvements in health-related quality of life (HRQOL). Achievement of RBC-TI and CyR with lenalidomide treatment was associated with extended survival and time to AML progression. Achievement of RBC-TI and hemoglobin response was additionally associated with HRQOL benefits. Recent data describing the impact of TP53 mutations and p53 expression on the prognosis of patients with del(5q) and the impact on response to lenalidomide are also discussed. The authors provide practical recommendations for the use of lenalidomide in patients with lower-risk del(5q) MDS.