Introduction: Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy and has an increasing incidence and prevalence globally, and proteasome inhibitors (PIs) form the backbone of some of our most effective regimens for all phases of this disease in fit and frail patients. Areas covered: Strong understanding of the proteasome complex is increasingly important as the rapid development of new PIs and innovative myeloma therapies complicate the use of old and new combination regimens. We focus herein on the pharmacodynamics and pharmacokinetics of the approved PIs and others in development, including their safety and efficacy in corresponding clinical studies. Expert opinion: Advancements such as the first oral PI, ixazomib, with a more convenient route of administration and improved toxicity profile led to an improved quality of life, patient compliance, and all-oral combination regimens which are efficacious for long-term management of standard and high-risk MM. Novel pan-PIs, such as marizomib, hold the promise of superior clinical activity due to irreversible targeting of all multicatalytic proteinase complex subunits. Development of clinically validated biomarkers of PI sensitivity/resistance is required to inform utilization of the most optimal and effective, rationally targeted PI treatments for all MM patients.