The clinical heterogeneity of the myelodysplastic syndromes (MDSs) relates to the recently discerned panoply of molecular abnormalities extant within this disease spectrum. Despite increasing recognition of these biologic abnormalities, very limited therapeutic options exist to exploit our increasing understanding of the molecular pathophysiology of MDS, with only 1 therapy (lenalidomide) particularly focused on a specific clinical patient subset (del(5q) cytogenetics) and 2 epigenetic modulators (azacitidine and decitabine) having been approved for treating these patients. This article will review the mutational and biologic landscape of these disorders, as well as the targeted therapeutics currently in clinical trials that are focused on attacking these features. Given the molecular complexity of these disorders and the limited repertoire of effective therapeutic agents, we will also discuss novel approaches attempting to determine potentially effective and personalized treatment options through complementary chemosensitivity and computerized signaling network screening for these disparate MDS patient subsets. Translational use of such resources, combined with the rapidly evolving next-generation molecular technologies, should prove useful in effectuating improved and more selective options for therapy.