The myelodysplastic syndromes (MDS) are frequently associated with clonally restricted cytogenetic abnormalities, but until recently, the molecular pathobiology underlying this diverse group of neoplastic bone marrow disorders has been largely obscure. During the last 10 years, many investigative groups have applied the formidable power of new molecular biology techniques to hunt for recurrent genetic alterations in MDS primary cells. Several genetic abnormalities, including mutations in RUNX1 (AML1), TET2, ASXL1, and TP53, have been discovered in a substantial fraction of MDS cases; genes rearranged or mutated less commonly in MDS include IER3, ATRX, RAS, and FLT3. Furthermore, haploinsufficiency and expression changes in RPS14, miR-145 and miR-146a, CDC25c, PP2A and SPARC in the absence of point mutations have also been implicated in MDS pathobiology. A major challenge will be to determine which of these mutations are causative "drivers" either in the development or progression of MDS, which might be therapeutically important because they predict response to treatment, and which are merely "passengers" along for the ride that alter phenotype but have no effect on the natural history of the disease. While the altered cellular biology of MDS is also increasingly well-understood, many mysteries remain. Abnormalities in iron regulation, microenvironment interactions, regulation of apoptosis, and oxidative damage/DNA repair may all play an important pathobiological role. By gaining a deeper understanding of the mechanisms of these complex and heterogeneous diseases, we will hopefully improve our ability to treat our patients with MDS beyond the therapies with limited effectiveness that are available at present.