Fifteen thousand new cases of multiple myeloma (MM) will occur in the United States in 2003, and the disease remains incurable. Diverse classes of chemotherapeutic agents induce cell death or apoptosis in MM cells; however, prolonged drug exposures ultimately induce chemoresistance. The mechanisms whereby MM cells resist drugs include alterations in intracellular signaling as well as adherence and cytokines in the bone marrow (BM) microenvironment. Novel agents that target the MM cell in its BM microenvironment are needed to both enhance anti-MM activity and prevent development of drug resistance. Delineation of cellular growth and apoptotic signaling pathways in MM cells may identify molecules that serve as novel therapeutic targets on the basis of interruption of MM cell growth or triggering of MM cell death.