Mitochondrial signaling is an important component of chemotherapy-induced apoptosis in cancer cells. Stress-inducers trigger the following sequence of events: Smac (second mitochondria-derived activator of caspases)/ DIABLO is released from the mitochondrial inner membrane to cytosol; activated/cytosolic Smac binds to XIAP, a protein belonging to the family of IAPs (Inhibitors of apoptosis proteins), thereby abrogating its inhibitory effects on caspase-9 and resulting in activation of caspase-9-mediated apoptotic cascade. IAPs play a key role in regulating the apoptotic signaling, and overexpression of IAPs confer chemoresistance in various tumor types. Here we show that a low molecular weight synthetic Smac mimetic (Novartis) by virtue of its ability to bind and inhibit IAPs, block the growth of MM cell lines, including those resistant to conventional agents including dexamethasone, melphalan or doxorubicin. Examination of purified patient MM cells demonstrated similar results. In contrast, no significant toxicity of Smac mimetic was noted against normal peripheral blood mononuclear cells. Moreover, Smac mimetic also did not affect viability of MM patient-derived bone marrow stromal cells (BMSCs). Treatment of MM cells overexpressing anti-apoptotic protein Bcl2 with Smac mimetic significantly decreases their viability. Importantly, combined treatment of MM cells with Smac mimetic and Tumor necrosis factor-related apoptosis inducing ligand (TRAIL, Apo-2 ligand) trigger synergistic anti-MM activity, without significant toxicity in normal cells. Finally, Smac mimetic enhances the anti-MM activity of conventional Melphalan. Collectively, these findings provide the rationale for clinical evaluation of Smac mimetic alone and in combination with Melphalan or TRAIL, to enhance MM cell killing, overcome drug-resistance, and improve patient outcome in MM.