Outcomes in multiple myeloma (MM) patients have improved in recent years owing to the introduction of new drugs. Among them, proteasome inhibitors and immunomodulatory imide drugs have become central in the management of newly diagnosed and relapsed MM. However, resistance to these classes of agents develops in most patients and ultimately leads to death from relapsed/refractory disease. A need exists for new classes of antimyeloma drugs, especially ones that are active in the multirefractory setting. The conventional drug development process, which involves extensive preclinical and clinical testing prior to assessment of clinical activity, has fallen short in delivering adequately safe and active novel drug candidates. HIV protease inhibitors such as nelfinavir are safe, US Food and Drug Administration-approved agents that have been shown to have potent antimyeloma activity in both preclinical models and patients with refractory disease. The repurposing of HIV protease inhibitors for treatment of MM is promising in light of their antimyeloma activity in conjunction with their global availability, established safety, and relatively low cost. This review will summarize the preclinical and clinical data available on HIV protease inhibitors for the treatment of refractory MM.