The paradigm for the treatment of monoclonal gammophaties has dramatically changed: based on the understanding of the complex interaction between tumor cells and bone marrow microenvironment and the signaling pathways that are deregulated in this process, a number of novel therapeutic agents are now available. For example, 3 novel agents with a targeted anti-multiple myeloma activity, have been FDA approved for the treatment of this disease, namely bortezomib, thalidomide, and lenalidomide. The success of targeted therapy in myeloma has led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias such as Waldenström's macroglobulinemia (WM), both in the preclinical settings and as part of clinical trials. Among them the role of proteasome inhibitors has been widely dissected providing the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM.