Diagnosing a myelodysplastic syndrome (MDS) can be challenging. Somatic mutations are common in MDS and might have diagnostic utility in patients with idiopathic cytopenias of undetermined significance (ICUS). However, using mutations to diagnose MDS is complicated by several issues: (1) no gene is mutated in most cases, (2) no mutated gene is highly specific for MDS, (3) clonal hematopoiesis is common in older individuals without disease, and (4) we lack outcome data for ICUS patients with clonal cytopenias of undetermined significance (CCUS). Despite these caveats, genetic sequencing can inform the diagnosis of MDS. CCUS patients more closely resemble patients with MDS than age matched controls with somatic mutations. Genetic testing can identify alternative diagnoses in cytopenic patients and help risk stratify those with proven MDS. While we cannot include somatic mutations in the diagnostic definition of MDS now, testing to recognize CCUS will help characterize outcomes in these diagnostically challenging patients.