Novel therapies that can target the multiple myeloma (MM) cell, the MM cell-patient bone marrow interaction, and the bone marrow milieu can overcome resistance to conventional therapy in preclinical models and clinical trials. Both proteasome inhibitor bortezomib and immunomodulatory drug Revimid (Celgene Corporation, Warren, NJ) have gone from laboratory bench to bedside in 3 to 4 years, and achieve responses even in patients with relapsed refractory MM. They are now undergoing clinical evaluation, alone and combined with conventional and novel therapies, for treatment of patients earlier in their disease course, and offer great promise to improve patient outcome in MM.