Experience from around the world now suggests that high response rates can be achieved in patients with multiple myeloma treated with high-dose therapy followed by hematopoietic stem cell transplantation. However, patients are destined to relapse and few, if any, are cured. Major obstacles to cure are the excessive toxicity noted after allografting in multiple myeloma, contaminating tumor cells in multiple myeloma autografts, and most importantly, the persistence of minimal residual disease after high-dose therapy and either allogeneic or autologous stem cell transplantation. In this context, strategies are being developed to decrease the toxicity of allografting and to enhance allogeneic anti-multiple myeloma immunity after transplantation to improve outcome. To improve autografting, better ablative regimens, more efficacious purging of tumor cells from autografts, and enhancement of autologous anti-multiple myeloma immunity post-transplantation are modalities being tested to enhance overall and event-free survival.