Population-based studies suggest a role for chronic immune stimulation and genetic factors in the causation of lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM). In this review we summarize and discuss our current understanding on etiology and pathogenesis of LPL/WM. We also highlight on gaps in the literature and propose future directions for population-based and molecular studies designed to expand our knowledge and uncover biological underpinnings of identified associations. Further, we address clinical implications and provide perspective on the relevance of these data for patient counseling and clinical follow-up.