Flow cytometric immunophenotyping has a well-established role in the diagnosis of mature B-cell lymphoid neoplasms. Identification of kappa or lambda immunoglobulin light chain restriction is a quick, inexpensive surrogate for clonality. In addition, simple algorithms based on B-cell expression of CD5 and CD10 have been widely adopted. However, this flow cytometric evaluation for B-cell neoplasms is often less than optimal. Kappa and lambda light chain staining can be difficult to interpret, disease entities don’t always follow the proposed algorithm, and sometimes other technologies are better able to establish a definitive classification. This presentation will outline strategies for flow cytometric assay optimization and interpretation. In addition, the use of flow cytometry as a triaging tool for cytogenetic fluorescence in situ hybridization and gene mutation assays will be discussed and illustrated with examples of hairy cell leukemia, high-grade–cell lymphoma with rearrangement of both MYC and BCL-2 genes, and lymphoplasmacytic lymphoma.