Waldenstrom macroglobulinemia (WM) is an IgM-secreting B-cell lymphoproliferative disorder, with strong familial predisposition. MYD88 L265P and CXCR4 WHIM mutations are common in WM and support the growth and survival of WM cells. Clinical manifestations of disease are related to both tumor cell infiltration and paraprotein production. Current treatment includes monoclonal antibodies, alkylating agents, nucleoside analogs, proteasome inhibitors, immunomodulatory drugs, and signal inhibitors. Short- and long-term toxicities should be weighed in treatment decisions with use of these agents. Elucidation of the signaling pathways involved in WM is helping to advance targeted therapeutics for WM and includes efforts directed at MYD88 and CXCR4 signaling.