Multiple myeloma (MM) remains an incurable malignancy, despite conventional and high-dose therapies, and novel biologically based treatment approaches are urgently needed. Recent studies have characterized the molecular mechanisms by which MM cell/host bone marrow (BM) interactions regulate tumor cell growth, survival, and migration in the BM milieu. These studies have not only enhanced our understanding of disease pathogenesis, but they have also provided the framework for a new treatment paradigm targeting the MM cell in its BM microenvironment to overcome drug resistance and improve patient outcome. Clinical trials are confirming the remarkable activity and improved tolerability of some of the new agents identified through this paradigm, providing exciting evidence of translational success in MM.