Outcome of patients with multiple myeloma (MM) has greatly improved with the use of autologous stem cell transplantation (ASCT) and new agents, such as immunomodulatory drugs (thalidomide and lenalidomide) and proteasome inhibitors (bortezomib). When compared to conventional chemotherapy, high-dose melphalan with ASCT significantly improved response rates and progression-free survival, while overall survival benefit was not consistent across all trials. ASCT is considered the standard treatment for patients who are younger than 65 years and who do not have limiting comorbidities. New, effective agents have been introduced as part of induction, consolidation and maintenance treatments within ASCT and in combinations with chemotherapy for patients not eligible for ASCT. The remarkable results obtained with these regimens are questioning the role of ASCT for newly diagnosed MM patients. This article aims to delineate the role of ASCT in the era of novel agents based on the results of recent clinical trials.