Waldenström's Macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow (BM) with lymphoplasmacytic cells, as well as detection of an IgM monoclonal gammopathy in the serum. WM is considered an incurable disease, with an overall median survival of only 5-6 years. The success of targeted therapy in multiple myeloma (MM) has led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias WM, both in the preclinical settings and as part of clinical trials. Among therapeutical options, first-line therapies have been based on single-agent or combination regimens with alkylator agents, nucleoside analogues, and the monoclonal antibody anti-CD20. Based on the understanding of the complex interaction between tumor cells and bone marrow microenvironment and the signaling pathways that are deregulated in WM pathogenesis, a number of novel therapeutic agents are now available; and demonstrated significant efficacy in WM. The range of the ORR to these novel agents is between 25-80%. Ongoing and planned future clinical trials include those using PKC inhibitors such as enzastaurin, new proteasome inhibitors such as carfilzomib, histone deacetylase inhibitors such as LBH589, humanized CD20 antibodies such as Ofatumumab, and additional alkylating agents such as bendamustine. These agents, when compared to traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM. This review will mainly focus on those novel agent that entered clinical trial for the treatment of WM.