Myelodysplastic syndromes (MDS) comprise a clinically and pathologically diverse collection of hematopoietic neoplasms, most commonly presenting with peripheral cytopenias typically in the context of bone marrow hypercellularity. Mechanistically, at least in the early phases of the disease, this apparently paradoxical picture is primarily due to ineffective hematopoiesis, which is accompanied by a variety of morphologic abnormalities in hematopoietic cells. The identification of recurrent, clinically relevant cytogenetic defects in MDS has spurred the research of molecular mechanisms that contribute to its inception as well as to the development of heterogeneous subtypes. Although conventional cytogenetic analyses remain a diagnostic mainstay in MDS, the application of contemporary techniques including molecular cytogenetics, microarray technologies and multiparametric flow cytometry may ultimately reveal new diagnostic parameters that are theoretically more objective and sensitive than current morphologic approaches. This review aims to outline the role of genetic and immunophenotypic studies in the evaluation of MDS, including findings that may potentially influence future diagnostic classifications, which could refine prognostication and ultimately facilitate the growth of targeted therapies.