Mutations in TP53 are observed in ∼20% of patients with myelodysplastic syndromes (MDS), with increased frequency seen in patients with a complex karyotype and cases of therapy-related MDS. TP53 mutations represent perhaps the single greatest negative prognostic indicator in MDS. Inferior outcomes are demonstrated with all approved treatment approaches, although hypomethylating agents remain the standard frontline treatment option. Although outcomes with allogeneic hematopoietic stem cell transplant are poor, it remains the only potentially curative therapy. Novel agents are required to improve outcomes in this molecular subgroup, with therapies that directly target the mutant protein and immunotherapies demonstrating greatest potential.