The chronic lymphoid leukemias comprise a number of biologically distinct neoplasms of mature lymphocytes. The availability of specific therapies for certain of these tumors makes accurate diagnosis imperative. In most cases, detailed immunophenotypic analysis of the chronic lymphoid leukemias permits specific classification and initiation of the most appropriate therapy. For example, the characteristic immunophenotype of B-cell chronic lymphocytic leukemia (CLL): CD5+, CD23+, FMC7-, CD20 dim+, clonal surface immunoglobulin (sIg) dim+, distinguishes it from another CD5+ B-cell lymphoproliferative disorder, mantle cell lymphoma, which typically displays the composite phenotype: CD5+, CD23-, FMC7+, CD20 bright+, clonal sIg bright+. Likewise, hairy cell leukemia has a characteristic immunophenotype: CD5-, CD11c bright+, CD25+, CD103+, which distinguishes it from other CD5- B-cell lymphoproliferative disorders, including the morphologically similar splenic lymphoma with circulating villous lymphocytes. Immunophenotypic analysis by flow cytometry may also identify clinically relevant subsets of patients within a diagnostic category of leukemia. Thus, in patients with CLL, deviation from the typical immunophenotype is associated with trisomy 12 and mixed-cell morphology. In summary, careful immunophenotyping by flow cytometry facilitates accurate diagnosis in the chronic lymphoid leukemias, and in some settings, may also offer additional therapeutically relevant information.