Myelodysplastic syndromes (MDS) comprise a group of underrecognized hematologic clonal malignancies with variable propensity for leukemic transformation that can present a diagnostic challenge because they lack hallmark symptoms. MDS can present with varying degrees of anemia, neutropenia, and thrombocytopenia, and at presentation can range from indolent to life threatening. The clinician should have a heightened level of suspicion when treating elderly patients and those with prior exposure to chemotherapy, radiation, and environmental toxins in the presence of unexplained cytopenias. Chronic anemia should not be considered a natural consequence of aging. Approximately 1 in 6 patients with unexplained anemia may have findings compatible with MDS, suggesting that MDS should be considered higher in the differential diagnosis. Primary care physicians are encouraged to conduct comprehensive evaluations to exclude non-MDS-related causes for persistent cytopenias. Patients with pancytopenia, bicytopenia, or any persistent and unexplained isolated cytopenia (and particularly unexplained macrocytic anemia) should be referred to a specialist to establish a diagnosis.