Simple SummaryCytological approaches have long been used in the diagnosis, prognosis, and management of acute myeloid leukemia (AML) and myelodysplastic neoplasms. Technological advances in molecular biology, in particular next-generation sequencing (NGS), have made it possible to establish a molecular list of several gene mutations in AML and MDS, within a matter of days. The combination of cytological approaches and NGS makes it possible to pinpoint genetic mutations and cancer cell survival and proliferation pathways, enabling better clinical management and improved prognosis of patients with acute leukemia and myelodysplastic neoplasms.AbstractFor decades, the diagnosis, prognosis and thus, the treatment of acute myeloblastic leukemias and myelodysplastic neoplasms has been mainly based on morphological aspects, as evidenced by the French-American-British classification. The morphological aspects correspond quite well, in a certain number of particular cases, to particular evolutionary properties, such as acute myelomonoblastic leukemias with eosinophils or acute promyelocytic leukemias. Advances in biology, particularly “classical” cytogenetics (karyotype) and molecular cytogenetics (in situ hybridization), have made it possible to associate certain morphological features with particular molecular abnormalities, such as the pericentric inversion of chromosome 16 and translocation t(15;17) in the two preceding examples. Polymerase chain reaction techniques have made it possible to go further in these analyses by associating these karyotype abnormalities with their molecular causes,CBFbetafusion withMYH11andPML-RARfusion in the previous cases. In these two examples, the molecular abnormality allows us to better define the pathophysiology of leukemia, to adapt certain treatments (all-transretinoic acid, for example), and to follow up the residual disease of strong prognostic value beyond the simple threshold of less than 5% of marrow blasts, signaling the complete remission. However, the new sequencing techniques of the next generation open up broader perspectives by being able to analyze several dozens of molecular abnormalities, improving all levels of management, from diagnosis to prognosis and treatment, even if it means that morphological aspects are increasingly relegated to the background.