The treatment of multiple myeloma has seen significant changes from the time of the initial use of cytotoxic agents such as melphalan, to the introduction of high-dose chemotherapy and stem cell transplantation, and most recently the era of novel targeted agents. These new drugs have rapidly become the mainstay of therapy of this disease and transformed the treatment paradigm, leading to improvements in survival and quality of life. Existing therapeutic options include agents such as thalidomide, bortezomib and lenalidomide, either used alone or in combination with standard agents, including glucocorticoids, and in conjunction with high-dose chemotherapy supported with stem cell transplantation. Several other targeted agents have demonstrated exciting preclinical activity, and are presently being tested in early Phase I and II clinical trials. This review summarizes the role of novel therapeutic agents in multiple myeloma, and the promising effect of multiple new agents in development.