Model cell lines are essential tools for investigating the biology and therapeutics of cancer. Approximately 1500 human hematopoietic neoplastic cell lines have been described, covering most major disease entities. Waldenström's macroglobulinemia (WM) is a rare incurable hematological neoplasm from which only three cell lines have been derived. Mindful that candidate tumor cell lines sometimes arise spuriously by viral immortalization of bystander cells, we review the extent to which WM cell lines portray established disease features in vitro. At closer inspection, it seems that none convincingly displays morphological, immunophenotypic, genotypic or biological features characteristic of WM. Rather it appears that two cell lines (WM1 and BCWM.1) are most probably Epstein-Barr virus-immortalized B-lymphoblastoid cell lines, derived from bystander B-cells. The third cell line (WSU-WM) carries the most common cytogenetic hallmark of Burkitt lymphoma, namely t(8;14)(q24;q32), while none have been shown to carry chromosome 6 deletions recently demonstrated as indicative of disease progression in this entity. In summary, although three WM cell lines are currently used as in vitro models, none convincingly pass muster.