Multiple Myeloma (MM) remains fatal despite all available therapies. Novel approaches that simultaneously target cellular mechanisms regulating growth and conferring chemoresistance in MM cells are needed. My studies have identified various novel treatments that target distinct components within the MM cells such as proteasomes (regulates protein degradation) or mitochondria (regulates cell respiration); therapeutic strategies combining these novels agents will block cell growth and increase cell death. Although individual agents show independent anti-MM activity, combinations of agents will be necessary to enhance cytotoxicity, abrogate drug resistance, and ultimately improve patient outcome.