Lenalidomide leads to high rates of erythroid transfusion independence in low and intermediate-1 risk International Prognostic Scoring System (IPSS) del(5q) myelodysplastic syndromes (MDS), with a considerable number of patients achieving complete and partial cytogenetic remissions. The median duration of transfusion independence is 2 years, mainly at the expense of neutropenia and thrombocytopenia in the first courses of therapy. At present, the optimal initial treatment dose has been determined to be 10 mg administered orally daily for 21 out of 28 days. In general, the effects in non-del(5q) disease can be divided by 50%: non-del(5q) patients show 50% of erythroid response, 50% of duration of response, and 50% incidence of grade 3 and 4 neutropenia and thrombocytopenia compared to del(5q) patients. Recent data suggest that the risk of acute myeloid leukemia (AML) progression of del(5q) patients is dependent on their individual risk factors before treatment initiation, including World Health Organization (WHO) prognostic scoring system parameters and TP53 mutations. These data also indicate that lenalidomide per se is not leukemogenic. Length of treatment can be tailored according to response, and patients who relapse during treatment might restart after a period of drug holiday. This article will also discuss combination strategies with lenalidomide in higher risk disease.