Waldenström macroglobulinemia (WM) is a lymphoplasmacytic lymphoma characterized by widespread involvement of the bone marrow (BM). The BM microenvironment serves as not only a site for disease involvement, but it also appears that the interaction of WM cells with the BM is essential for the pathogenesis of WM. The BM microenvironment consists of the cellular and noncellular compartments. The BM has been shown to regulate cell proliferation, cell cycle, and drug resistance as well as cell dissemination and cell trafficking of WM cells. A better understanding of the role of the BM microenvironment in the pathogenesis of WM can help guide better therapeutic strategies that can target the tumor clone and also regulate the BM microenvironment.