Multiple myeloma (MM) represents the second-most common hematologic malignancy. In the 1980s, induction therapy with alkylating agents, such as anthracyclines and steroids, as well as high-dose chemotherapy followed by autologous stem cell transplantation were the main therapeutic approaches for MM. Since the introduction of more effective drugs, such as proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies and histone deacetylase inhibitor, the new therapeutic algorithm allows of achieving a significantly improvement of prognosis. Numerous regimens, which differently combine these new agents, have been developed and tested in clinical trials. The results of these new regimens are reported each year. In this variegated new contest, old chemotherapeutic drugs still maintain an overriding weight, especially when beneficially combined with new drugs. Also, this is particular true in specific situations, such as extramedullary manifestations, in which tumor mass reduction becomes an urgent clinical need, or in case of chemotherapy-induced stem-cell mobilization. Moreover, melphalan represents the gold standard conditioning regimen since 2002, either alone or, possibly in the next future, in combination with busulfan. Finally, new chemotherapeutic agents with new mechanisms of action, such as melflufen, are in early experimental phase.