26S proteasomes degrade mostly proteins marked by polyubiquitination and is responsible for the majority of protein degradation in the cells. Consequently, proteasome inhibitors are toxic to many cells and proteasome inhibitors have become a preferred therapy for the blood cancer multiple myeloma. Bortezomib has been used to treat more than 400,000 myeloma patients since its FDA approval in 2004, and in 2012, another proteasome inhibitor, Carfilzomib, was also approved to treat refractory myeloma patients. Despite these encouraging progresses, drug resistance remains a prominent challenge to myeloma therapy using these inhibitors. In fact, all patients will eventually relapse with a highly advanced lethal disease. Therefore, it is important to understand the mechanisms of such resistance and to develop therapeutic approaches. There have been tremendous research effort on this topic, and it is currently clear that resistance to the proteasome inhibitor treatment can occur by several diverse mechanisms, all rescuing a particular step in the killing pathway elicited by proteasome inhibition. This editorial aims at reviewing how proteasome inhibition kills myeloma cells and how cells may evolve methods to inactivate critical steps of the killing mechanism and develop drug resistance. This information will be useful to identify crucial targets for drug development to overcome such resistance.