Multiparameter flow cytometry (MFC) is valuable in the diagnosis and monitoring of most hematological malignancies. Although the assessment of cellular infiltrates in Waldenström macroglobulinemia (WM) relies on morphology and immunohistochemistry grounds, there is evidence pointing to the clinical significance of MFC in this disease. Herein, the authors review immunophenotypic patterns of B-cell development, the antigen profile of the WM clone and its normal B-cell counterpart, the clinical applicability of MFC in the differential diagnosis of immunoglobulin M–secreting lymphoproliferative disorders and monoclonal gammopathies, and its potential role in detecting minimal residual disease and monitoring treatment efficacy in WM.