Multiple myeloma (MM) is a B-cell malignancy that comprises 10% of all hematopoietic cancers. Even with aggressive chemotherapeutic regimens, the emergence of chemotherapy-resistant disease remains a notable therapeutic challenge, and there is no cure. The recent advances in understanding the mechanisms critical for MM cell growth and survival in its microenvironment have provided novel therapeutic targets to improve patient outcomes. Based on preclinical studies, the novel targeted agents thalidomide and its analogs, bortezomib and arsenic trioxide, have been evaluated in phase I and II clinical studies in refractory or relapsed MM and have demonstrated significant antimyeloma activity. Ongoing studies will further define their usefulness as primary therapies at earlier stages of disease. These innovative therapies for MM represent a new treatment paradigm, targeting tumor cells and their microenvironments to achieve greater tumor cytoreduction and potentially a cure.