Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of the bone marrow with lymphoplasmacytic cells and the detection of an IgM monoclonal gammopathy in the serum. WM is considered an incurable disease, with a median overall survival of 87 months. The success of targeted therapy in multiple myeloma has led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias, including WM, both in the preclinical settings and as part of clinical trials. Among therapeutic 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 WM tumor cells and the bone marrow microenvironment, and the signaling pathways that are deregulated in WM pathogenesis, a number of novel therapeutic agents are now available and have demonstrated significant efficacy in WM. The range of the overall response rate for these novel agents is between 25 and 96%. Ongoing and planned future clinical trials include those using protein kinase C 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 with traditional chemotherapeutic agents, may lead in the future to higher responses, longer remissions and better quality of life for patients with WM. This article will mainly focus on those novel agents that have entered clinical trials for the treatment of WM.