The myelodysplastic syndromes (MDS) are a heterogeneous constellation of hematologic malignancies characterized by aberrant differentiation and clonal expansion of abnormal myeloid cells that initially manifest with ineffective hematopoiesis and consequent cytopenias. The prognosis of MDS is variable and depends on clinical and hematologic parameters, cytogenetic and molecular findings, as well as comorbidities. Gene sequencing studies have uncovered remarkable genomic complexity within MDS, based on the presence of recurrent and sometimes co-operating mutations in genes encoding proteins that play a role in numerous biologic pathways. Although the treatment of MDS is currently limited to the use of hypomethylating, immunomodulatory, or erythropoiesis-stimulating agents, improved understanding of the molecular underpinnings of its pathophysiology has led to the development of multiple targeted treatments that are poised to be added to the therapeutic armamentarium. This review will focus on the role of mutations in the pathogenesis, diagnosis, and prognosis of MDS and how the discovery of clonal hematopoiesis of indeterminate potential (CHIP) might impact the utility of detecting mutations in the diagnosis of MDS.