Multiple myeloma remains largely incurable despite conventional and high-dose therapies, and so novel biologically based treatment approaches are urgently required. Recent studies have characterized the molecular mechanisms by which multiple myeloma cell-host bone-marrow interactions regulate tumour cell growth, survival and migration in the bone-marrow microenvironment. These studies have not only enhanced our understanding of disease pathogenesis, but have also provided the framework for a new treatment model that targets the multiple myeloma cell in its bone-marrow microenvironment to overcome drug resistance and improve patient outcome.