The myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders of ineffective hematopoiesis that characteristically demonstrate peripheral blood cytopenia, bone marrow hypercellularity, and morphologically defined dysplasia of one or more hematopoietic lineages. Classical metaphase cytogenetics and judicious use of fluorescence in situ hybridization play central roles in the contemporary diagnosis and classification of MDS. An abundance of recent molecular studies are beginning to delineate additional genetic and epigenetic aberrations associated with these disorders. These alterations affect diagnosis, prognosis, and therapy, and with this understanding classification systems are evolving from a primarily hematological and morphological basis toward a multifactorial appreciation that includes histomorphology, metaphase cytogenetics, and directed molecular studies. In the present health-care environment, it is critical to develop a cost-effective, efficient testing strategy that maximizes the diagnostic potential of even limited specimens. Here, we briefly review the classical genetic approach to MDS, outline exciting new advances in the molecular understanding of this heterogeneous group of hematological neoplasms, and discuss how these advances are driving the evolution of classification and prognostic systems. Rapidly growing understanding of the genetic basis of MDS holds much promise for testing, and here we provide a frame of reference for discussion of current testing protocols and for addressing testing modalities likely to enter clinical practice in the near future.