Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of clonal plasmablast/plasma cells within the bone-marrow. It is well established that the bone-marrow microenvironment has a pivotal role in providing critical cytokines and cell-cell interactions to support the growth and survival of the MM tumor clone. The pathogenesis of MM is, however, only fragmentarily understood. Detailed genomic analysis reveals a heterogeneous and complex pattern of structural and numerical chromosomal aberrations. In this review we will discuss some of the recent results on the functional role and potential clinical use of the IGF-1R, one of the major mediators of growth and survival for MM. We will also describe some of our results on epigenetic gene silencing in MM, as it may indeed constitute a novel basis for the understanding of tumor initiation and maintenance in MM and thus may change the current view on treatment strategies for MM.