The availability of inexpensive next-generation DNA sequencing assays is changing hematology practice. Well-designed sequencing panels can provide confirmation of the presence of a clonal disorder in patients with unexplained cytopenias, and mutation analysis influences prognosis in those with an established diagnosis of myelodysplastic syndromes (MDS). Sequencing results may in some cases suggest an alternate or concomitant diagnosis or may make a patient eligible for a clinical trial of a targeted therapy. However, clonal hematopoiesis is common in older patients and this, as well as technical challenges, can make diagnosis difficult. Dr. Steensma will discuss appropriate uses of molecular testing in patients with unexplained cytopenias and with MDS, outline key unanswered questions, and review several illustrative cases.