The development of multiple myeloma (MM) is a complex multi-step process involving both early and late genetic changes in the tumor cell as well as selective supportive conditions by the bone marrow (BM) microenvironment. Indeed, it is now well established that MM cell-induced disruption of the BM homeostasis between the highly organized cellular and extracellular compartments supports MM cell proliferation, survival, migration and drug resistance through activation of various signaling (for example, PI3K/Akt, JAK/Stat-, Raf/MEK/MAPK-, NFkappaB- and Wnt-) pathways. Based on our enhanced understanding of the functional importance of the MM BM microenvironment and its inter-relation with the MM cell resulting in homing, seeding, proliferation and survival, new molecular targets have been identified and derived treatment regimens in MM have already changed fundamentally during recent years. These agents include thalidomide, its immunomodulatory derivative lenalidomide and the proteasome inhibitor bortezomib, which mediate tumor cytotoxicity in the BM milieu. Ongoing studies are further delineating MM pathogenesis in the BM to enhance cytotoxicity, avoid drug resistance and improve patient outcome.