Multiple Myeloma (MM) remains an incurable plasma cell malignancy in the bone marrow (BM) despite conventional therapies as well as high-dose therapies with stem cell support. Therefore novel biologically-based therapeutic approaches are required. Recently, intensive laboratory and preclinical studies have identified and validated therapeutic molecular targets in MM. In particular, recognition of the biologic significance of the BM microenvironment in MM pathogenesis and as a potential target for novel therapeutics has derived several promising approaches. Novel FDA approved agents including thalidomide/thalomid, its immunomodulatory derivatives lenalidomide/Revlimid, and proteasome inhibitor bortezomib/Velcade are directed at molecular targets not only in MM cells but also in its BM milieu, and have already achieved promising results in clinical studies. Here we discuss the mechanisms of action of these novel drugs and their clinical application, alone or combined with conventional or novel drugs.