Advances in the understanding of the cellular and molecular derangements involved in the initiation and progression of multiple myeloma are beginning to be translated into novel therapeutic approaches. The myeloma stem cell has been under intense scrutiny regarding its normal B-cell counterpart. Oncogenes, tumor-suppressor genes, and cell-survival genes have all been found to be dysregulated in some myeloma patients. Growth factors, especially interleukin-6, appear to be critical for disease progression, and interruption of autocrine and paracrine loops has been achieved with resultant inhibition of myeloma cell growth. Mechanisms of drug resistance and the implications of the multidrug resistance phenotype are just beginning to be understood. High-dose therapeutic regimens with autologous peripheral blood stem cell or allogeneic bone marrow rescue are rigorously being studied with an emphasis on exploiting the graft-versus-myeloma effect. Pamidronate, a second-generation bisphosponate, has been shown to be effective at decreasing adverse skeletal events in patients with advanced myeloma. The topoisomerase 1 inhibitor, topotecan, has shown activity in an initial study.