Multiple myeloma (MM) remains an incurable disease for most patients, with a median survival of 4 to 5 years. High-dose chemotherapy followed by transplantation has resulted in improvement in response rates and survival compared with conventional therapy, but relapse is nearly universal and not all patients are candidates for this option of aggressive treatment. Standard therapeutic strategies for newly diagnosed patients not eligible for transplantation include pulsed high-dose dexamethasone, melphalan with prednisone, and vincristine in combination with doxorubicin and dexamethasone, as well as other combinations of alkylating agents. Emerging therapies under clinical investigation for first-line therapy include thalidomide, the thalidomide analog lenalidomide, and the proteasome inhibitor bortezomib alone and in combination with other agents, particularly dexamethasone. At an interim analysis, thalidomide combined with melphalan and prednisone was shown to induce a complete or near complete remission (CR) rate of 28% and overall (complete+partial) response rate of 77% in elderly patients generally not eligible for transplantation. These results are comparable to those obtained with high-dose therapy and may obviate transplantation in these patients. Induction therapy with bortezomib-based combinations induces complete and near complete remissions in a similar proportion of patients. These regimens include bortezomib and dexamethasone alone and in combination with doxorubicin, thalidomide, or melphalan. Use of thalidomide or bortezomib does not preclude stem cell harvest. Survival benefits need to be firmly established before these novel regimens emerge as the new standard of care for newly diagnosed disease. However, front-line treatment with combinations involving these agents is a promising strategy that may improve the standard of care for patients both eligible and ineligible for stem cell transplantation.