Many novel agents and new combinations (including bortezomib, thalidomide, and lenalidomide) have been developed in recent years for the treatment of multiple myeloma (MM), creating major shifts in therapeutic management. Achieving complete response (CR)/near CR (nCR) generally serves as a reliable clinical surrogate for overall treatment outcome, ie, prolonged survival. Indeed, some newer induction regimens are yielding similar median time to disease progression effects compared with transplantation. Thus, it can be a dilemma whether a patient with CR/nCR needs to be subjected to the potential morbidity associated with transplantation after induction therapy. Combining new agents with chemotherapy-based regimens appears to offer higher overall response and CR/nCR rates than similar combinations that do not include chemotherapy. We review the preclinical and clinical rationale for combining bortezomib with pegylated liposomal doxorubicin for the treatment of MM. The synergistic interaction in sensitizing each other toward myeloma cells in vitro and their complementary in vivo activities have justified clinical studies. We summarize data for completed and ongoing phase I/II trials of this combination. To date, results have been sufficiently encouraging to initiate an international, multicenter, randomized, phase III trial comparing bortezomib with or without pegylated liposomal doxorubicin in patients with relapsed/refractory MM. The results of this trial will confirm whether the rationale for combining bortezomib with pegylated liposomal doxorubicin is validated by improved clinical outcome, ie, improved time to progression, for patients with MM.