Acute leukemias (involving the myeloid and lymphoid lineages) and the related myelodysplastic and myeloproliferative syndromes are an extremely heterogeneous group of clonal neoplastic disorders. Traditionally, these diseases were classified solely by morphologic and cytochemical criteria, as originally championed in the 1976 French-American-British Group proposal. Since 1976, however, phenomenal scientific advances have provided new insights into the biology and genetics of the acute leukemias and myeloproliferative/myelodysplastic diseases. Immunophenotyping approaches have begun to supplant more traditional cytochemical assays for lineage determination, and cytogenetic and molecular genetic studies led to the identification and cloning of the genes involved in a large number of the recurrent genetic abnormalities in these diseases. New automated molecular technologies, reviewed in this article, now allow rapid and sensitive detection of these genetic abnormalities in leukemic cells. Such immunophenotyping and molecular genetic information is now considered crucial for both diagnostic and therapeutic decision-making. As our scientific knowledge and diagnostic sophistication increases, classification schemes for these disorders based solely on morphologic features are increasingly seen as unsatisfactory. This review highlights progress in the development of new morphologic classification schemes for the acute leukemias that integrate critical clinical, biologic, and genetic features.