The etiology of Waldenstrom's macroglobulinemia (WM) is unknown. A possible role for genetic factors has been suggested by reports of familial clustering of WM. However, it is not yet possible to define the proportion of all WM that occurs in the familial setting. Review of the data on the 12 families published since 1962 suggests that familial WM may differ from sporadic disease in certain respects. Among these families, there is a pronounced occurrence of a variety of immunologic abnormalities in the relatives of WM cases. Notably, the prevalence of IgM monoclonal gammopathy (IgM MG) in first-degree relatives of WM cases was reported to be as high as 6.3%, representing a 10-fold increase relative to general population estimates. IgM MG has been shown to progress to WM at a rate of approximately 1.5% per year in a large case series; whether this rate of progression is altered in familial WM is unknown. Although limited by small numbers and a lack of systematic ascertainment and evaluation, these data are intriguing and provide a compelling basis for further study and systematic investigation of WM in families. Semin Oncol 30:146-152. This is a US government work. There are no restrictions on its use.