Melphalan in combination with glucocorticoid steroids has been an important first-line treatment option for multiple myeloma (MM) for over 40 years, but response rates have been only 50-60%, with less than 5% complete remissions (CRs). More intensive combinations of chemotherapy such as vincristine, Adriamycin and Dexamethasone (Dex) (VAD) improved objective response rates to 40%-70%, with 10-17% complete responses, but overall survival (OS) was not significantly improved. High-dose therapy with autologous hematopoietic stem cell transplantation (AHCT) has improved OS by approximately 12 months in three prospective randomized trials, but is not available to many patients. More recently, novel therapies thalidomide, the immunomodulatory thalidomide analogue Revlimid, and the proteasome inhibitor bortezomib have demonstrated significant activity to overcome drug resistance in patients with relapsed and refractory MM. Early results indicate that these novel therapeutics have even more impressive activity in combination with conventional therapies prior to AHCT, as well as following AHCT. Furthermore, these novel therapies should be more widely available to most patients with MM.