Defined by isolated del 5q and no excess of marrow blasts, the "5q- syndrome" is a specific type of myelodysplastic syndrome (MDS) with particular characteristics, including severe anemia, frequent thrombocytosis, typical dysmegakaryopoiesis and favorable outcome. Its pathogenesis remains uncertain, in particular the role of inactivation of gene(s) situated in 5q. It should be differentiated from other MDS with del 5q having an excess of marrow blasts and/or additional cytogenetic abnormalities, which carry a poor prognosis. Until the advent of lenalidomide, repeated RBC transfusions were generally the only treatment of the 5q- syndrome, which was resistant to other therapeutic approaches. Lenalidomide can lead to RBC transfusion independence in at least two thirds of cases of the 5q- syndrome, two thirds of those responses persisting after 2 years of treatment. Importantly, not only reversal of anemia but also frequent complete pathological and cytogenetic responses are obtained. Grade 3 or 4 neutropenia and thrombocytopenia, especially during the first 6 to 8 weeks of treatment, are the major side effect of lenalidomide, justifying close monitoring of blood counts and regular patient visits. Preliminary results suggest that lenalidomide is also very active in MDS with del 5q other than the 5q-syndrome. Although its mechanism of action remains uncertain, lenalidomide appears to target specifically the del 5q clone. By doing this, lenalidomide may have an effect on disease course and survival, which is currently being assessed in clinical trials.