Introduction: Therapeutic options for myelodysplastic syndromes (MDS) are limited to hypomethylating agents (HMA) and lenalidomide. Rigosertib, a small molecule which blocks RAS-mediated activation of proteins containing a common RAS binding domain, appears to be a promising novel drug.Areas covered: Discovery, mechanism of action of rigosertib, and results of clinical trials are described. More than 500 patients have been treated and the safety, pharmacokinetics, and efficacy of rigosertib are summarized. These studies are placed in the context of the history of therapeutic development in MDS and the promise of new, tailored treatments based on emerging knowledge of the heterogeneity and molecular biology of the disease.Expert opinion: In summary, the Phase III study failed to meet the primary endpoint but clearly showed significant improvement in survival in a subset of very high risk MDS patients who were primary HMA failures. A new Phase III trial designed to validate these findings is now ongoing. Oral rigosertib, in a Phase II trial, produced transfusion independence in similar to 35% patients with lower risk MDS with or without recombinant erythropoietin. A methylation based signature appears to distinguish between the two groups. Validation of these early encouraging observations through future clinical trials is eagerly anticipated.