The standard treatment approach to symptomatic myeloma consists of induction therapy, consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplantation in appropriate patients, maintenance therapy, and salvage therapy. Salvage therapy is of particular importance because not all patients respond to primary therapy, and relapse is virtually universal in responding patients. Newer agents such as thalidomide, bortezomib, and lenalidomide are very active in patients with relapsed or refractory disease. Their use singly and in combination results in excellent cytoreduction including complete remissions in patients relapsing - even after extensive prior therapy. These novel agents have been usually used as salvage therapy in patients relapsing after standard treatment options including transplantation; a setting in which they are thought to improve survival. However, there is an increasing trend to start using them early in the course of the disease; for induction therapy. While early deployment of these agents is certainly associated with high-response rates, evidence that this improves long-term outcome (survival) in patients who subsequently undergo intensive therapy and transplantation is lacking. Toxicity, expense, and possible long-term consequences on the biology of the disease (for example, development of refractory relapse) remain a concern. The most appropriate use of newer agents such as lenalidomide is as salvage therapy of relapsed or refractory disease, and their use as part of induction therapy should be confined to clinical trials until additional data and long-term follow-up are available.