BACKGROUND: Multiple myeloma (MM) is a malignant plasma cell disorder with a median survival of three years. Despite the development of numerous conventional chemotherapy regimens and interferons, there has been little progress in improving the survival of patients with MM. Very high-dose chemoradiotherapy and autologous or allogeneic hematopoietic stem cell transplantation (HSCT) can result in high complete remission rates, even in patients with advanced disease. METHODS: A prospective, randomized study has shown that autologous HSCT results in superior response rates, progression-free survival, and disease-free survival compared with conventional chemotherapy. This is the first real advance in the treatment of this disease in 30 years. Unfortunately, few, if any, patients with MM who receive autologous HSCT are cured. RESULTS: Allogeneic HSCT can be curative for a fraction of patients with MM. However, very high transplant-related morbidity and mortality limit the application of allografts to younger patients with compatible donors. CONCLUSIONS: Challenges for the future include the development of less intensive or more disease-specific chemotherapy regimens that preserve the antitumor activity but are less toxic, improvement in the control of graft-vs-host disease in the case of allografts and, for autologous graft recipients, the development of vaccines and cytotoxic lymphocytes to augment a graft vs myeloma effect.