In the past years, new developments have occurred both in the understanding of the biology of Waldenstrom Macroglobulinemia (WM) and in therapeutic options for WM. WM is a B-cell disorder characterized primarily by bone marrow infiltration with lymphoplasmacytic cells, along with demonstration of an IgM monoclonal gammopathy. Despite advances in therapy, WM remains incurable, with 5-6 years median overall survival of patients in symptomatic WM. Therapy is postponed for asymptomatic patients, and progressive anemia is the most common indication for initiation of treatment. The main therapeutic options include alkylating agents, nucleoside analogues, and rituximab. Studies involving combination chemotherapy are ongoing, and preliminary results are encouraging. No specific agent or regimen has been shown to be superior to another for treatment of WM. As such, novel therapeutic agents are needed for the treatment of WM. In ongoing efforts, we and others have sought to exploit advances made in the understanding of the biology of WM so as to better target therapeutics for this malignancy. These efforts have led to the development of several novel agents including the proteasome inhibitor bortezomib, and several Akt/mTor inhibitors, perifosine and Rad001, and immunomodulatory agents such as thalidomide and lenalidomide. Studies with monoclonal antibodies are ongoing and promising including the use of alemtuzumab, SGN-70, and the APRIL/BLYS blocking protein TACI-Ig atacicept. Other agents currently being tested in clinical trials include the PKC inhibitor enzastaurin, the natural product resveratrol, as well as the statin simvastatin. This report provides an update of the current preclinical studies and clinical efforts for the development of novel agents in the treatment of WM.