The treatment of multiple myeloma has undergone significant changes in the past few years. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, has dramatically improved the outcome of this disease and considerably increased the treatment options available. Several trials have shown the advantages linked to the use of novel agents both in young patients, who are considered eligible for transplantation, and elderly patients, for whom a conventional therapy should be considered. These novel agents may increase the efficacy of autologous stem cell transplantation with deeper and long-lasting response. In the transplant setting, different novel agent combinations have proved to be superior to the traditional vincristine-doxorubicin-dexamethasone. Similarly, novel agents have also changed the treatment paradigm of patients not eligible for transplantation, thus replacing the traditional melphalan-prednisone approach. Preliminary data also support the role of consolidation and maintenance therapy to further improve outcomes. This article provides an overview of the latest strategies, including novel agents used to treat patients with multiple myeloma, both in the transplant and nontransplant settings.