No survival advantage of autologous stem cell transplantation (ASCT) has been documented for patients older than 65 years, and in the era of thalidomide (Thalomid), bortezomib (Velcade), and lenalidomide (Revlimid), ASCT has a diminished role in the front-line treatment of older patients with myeloma. For these individuals and for those who cannot or choose not to undergo ASCT, the initial treatment regimens now recommended by both the National Comprehensive Cancer Network and the International Myeloma Working Group are melphalan (Alkeran)/prednisone/thalidomide (MPT), bortezomib/melphalan/prednisone (VMP), and lenalidomide/low-dose dexamethasone. Melphalan/prednisone should no longer be considered the reference treatment, although it may be appropriate for a small number of patients with serious comorbidity and/or poor performance status. Advantages of VMP over MPT include rapid response, high rates of complete response, patient compliance, and more extensive evidence of efficacy in patients with certain cytogenetic abnormalities. Lenalidomide/low-dose dexamethasone is particularly appropriate for patients with preexisting neurotoxicity and those who wish to postpone ASCT. Toxicity profiles differ among the newly established and emerging regimens, and oncology teams must take care to apply the appropriate risk management measures, including dose reduction where necessary.