Van Den Berghe established 5q- syndrome as a discrete clinical entity in 1974 when he described patients with macrocytic anaemia, thrombocytosis, dyserythropoiesis, hypolobulated megakaryocytes and an interstitial deletion within chromosome 5q. With del(5q) as the sole cytogenetic abnormality, 5q- syndrome represents an opportunity to define precisely the molecular defect(s) underlying the pathogenesis of this disease. The commonly deleted region in 5q- syndrome, which is distinct from that in patients with complex cytogenetic changes that include del(5q), includes the ribosomal protein S14 locus and it has been proposed that that loss of an RPS14 allele accounts for the 5q- syndrome phenotype. However, this hypothesis fails to explain the growth advantage of the 5q- syndrome clone and it is evident that ribosomal protein defects are not specific to 5q- syndrome, as they are found in other bone marrow failure syndromes. Lenalidomide therapy leads to normalization of both haematological and cytogenetic parameters in the majority of 5q- syndrome patients. This review examines the potential role of several genes, including RPS14, in the pathogenesis of the 5q- syndrome and recent advances in clinical management, with particular emphasis on the role and mechanism of action of lenalidomide.