Multiple myeloma (MM) is a hematological disease that remains largely incurable. The introduction of proteasome inhibitors (PIs) at the turn of the century led to prolonged survival of patients, though most will inevitably develop resistance over successive treatments. It is of great clinical interest, then, to resensitize MM cells to PIs. This review discusses some of the most well-established resistance pathways, such as alterations in the proteostasis network and the bone marrow microenvironment. Novel targets are highlighted and placed in the context of potential treatment strategies where applicable.