Abstract Since the inception of infusional vincristine/doxorubicin/pulsed dexamethasone (VAD) for the treatment of multiple myeloma, anthracyclines have remained an important class of antimyeloma agents. More recently, the introduction of pegylated liposomal doxorubicin with improved pharmacokinetic characteristics has led to the development of newer anthracycline-containing regimens with improved toxicity profiles. Bortezomib, a first in class reversible inhibitor of the proteasome, has also emerged as an important novel agent for the treatment of multiple myeloma and is currently approved for patients with relapsed/refractory disease progressing after 1 previous therapy. Although both classes of agents have potent proapoptotic activity, they also induce activation of an antiapoptotic prosurvival program that limits their own efficacy, a process known as inducible chemotherapy resistance. Importantly, in preclinical studies, each of these drugs has been shown to attenuate chemotherapy resistance induced by the other, and combinations of the 2 have demonstrated striking synergistic activity. Furthermore, early phase I/II clinical trials have shown impressive activity of pegylated liposomal doxorubicin and conventional doxorubicin in combination with bortezomib in patients with newly diagnosed and relapsed/refractory myeloma. Phase II/III clinical trials evaluating these regimens in patients with newly diagnosed and relapsed/refractory disease have recently completed accrual and will better define the role of these combinations in myeloma therapy. Herein, we review the preclinical data supporting the use of bortezomib with anthracyclines and the promising clinical data with these combinations.