Treatment approaches for newly diagnosed myeloma have changed considerably during the past decade, along with a better understanding of the disease heterogeneity. Availability of new drug classes such as proteasome inhibitors and immunomodulatory drugs, and use of these drugs in combinations have led to higher response rates and deeper responses in the vast majority of patients with newly diagnosed myeloma. In addition to improved efficacy, these regimens are tolerated better than those with conventional chemotherapy drugs, which have reduced the early mortality seen in MM, while allowing for successful stem cell collection in patients undergoing stem cell transplant consolidation. Ongoing clinical trials with newer drugs such as monoclonal antibodies are being explored as options for newly diagnosed MM. The optimal regimen continues to evolve and is often dictated by the intent to transplant, age and comorbidities. Despite the increasing response rates seen with the new regimens, autologous stem cell transplantation remains an effective modality for consolidation, further deepening the responses seen with the initial therapy. Post-transplant approaches have further added to the efficacy of this platform with both post-transplant consolidation and maintenance demonstrating value in clinical trials. Currently, the combination of an effective initial therapy followed by one or two autologous stem cell transplants, with or without consolidation followed by maintenance appear to provide the maximum benefit in terms of duration of disease control for patients with newly diagnosed MM.