BACKGROUND Novel agents and the availability of autologous stem-cell transplantation have revolutionized the treatment of patients with multiple myeloma. First-generation novel agents namely thalidomide, lenalidomide, and bortezomib have significantly improved response and survival of patients. Second-generation novel agents such as pomalidomide, carfilzomib, and monoclonal antibodies are being tested both in the newly diagnosed and relapse settings, and results are promising. METHODS In this review article, the main results derived from Phase III trials with thalidomide, lenalidomide, and bortezomib for the treatment of myeloma patients, both at diagnosis and at relapse, are summarized. Data about second-generation novel agents such as pomalidomide and carfilzomib are also reported. Newer effective drugs currently under investigation and the promising results with monoclonal antibodies are described. CONCLUSIONS The availability of new effective drugs has considerably increased the treatment options for myeloma patients. A sequential approach including induction, transplantation (when possible), consolidation, and maintenance is an optimal strategy to achieve disease control and prolong survival. Despite these improvements, the best combination, the optimal sequence, and the proper target of newer drugs need to be defined.