In vitro and in vivo models have been developed that have allowed for delineation of mechanisms of multiple myeloma (MM) cell homing to bone marrow (BM); tumor cell adhesion to extracellular matrix proteins and BM stromal cells; and cytokine-mediated growth, survival, drug resistance, and migration within the BM milieu. Delineation of the signaling cascades mediating these sequelae has identified multiple novel therapeutic targets in the tumor cell and its BM microenvironment. Importantly, novel therapies targeting the tumor cell and the BM, as well as those targeting the tumor cell or BM alone, can overcome the growth, survival, conventional drug resistance, and migration of MM cells bound to BM using both in vitro and in vivo severe combined immunodeficiency mouse models of human MM. These studies have translated rapidly from the bench to the bedside in derived clinical trials, and have already led to the United States Food and Drug Administration approval of the novel proteasome inhibitor bortezomib for treatment of relapsed/refractory MM. Novel agents will need to be combined to enhance cytotoxicity, avoid development of drug resistance, and allow for use of lower doses in combination therapies. Genomics, proteomics, and cell signaling studies have helped to identify in vivo mechanisms of sensitivity versus resistance to novel therapies, as well as aiding in the rational application of combination therapies. These studies have therefore provided the framework for a new treatment paradigm targeting the MM cell in its BM milieu to overcome drug resistance and improve patient outcome in MM.