High-dose melphalan (Alkeran) and autologous stem cell transplantation are commonly incorporated into the initial line of therapy for patients newly diagnosed with multiple myeloma. This option is usually offered to patients less than 70 years old who have no major comorbidities. Selected older patients and those with mild to moderate organ dysfunction may also be reasonable candidates. An important goal of induction therapy is to achieve remission; a complete response predicts longer survival after transplantation. The regimens for initial therapy that are based on level 1 evidence and consensus include bortezomib (Velcade)/dexamethasone, bortezomib/doxorubicin/dexamethasone, bortezomib/thalidomide (Thalomid)/dexamethasone, and lenalidomide (Revlimid)/low-dose dexamethasone. Recent studies have provided guidance for choosing among these regimens for patients with cytogenetic abnormalities, renal disease, and other negative prognostic indicators. There is evidence from phase III studies that use of thalidomide/dexamethasone and bortezomib-based induction regimens can translate into significantly better survival after transplantation compared with the older chemotherapy regimens.