Multiple myeloma (MM) is a cancer of plasma cells, characterized by abundant synthesis of monoclonal immunoglobulins and/or free light chains. Although MM remains incurable, median overall survival has considerably improved over the past 2 decades largely due to the introduction of novel agents, including proteasome inhibitors (PIs) and immunomodulatory drugs. Bortezomib, a reversible boronate PI, was the first Food and Drug Administration–approved PI in MM and subsequently mantle cell lymphoma. Carfilzomib and ixazomib, the former an irreversible epoxyketone and the latter an orally bioavailable reversible PI, have been subsequently approved in MM. Altogether, these drugs represent the first effort to disrupt protein homeostasis as a therapeutic strategy in MM. Although effective, de novo resistance is a recognized phenomenon, and acquired resistance to PI is common, prompting the development of biology-based combination therapies. Based on laboratory evidence of increased, constitutive proteotoxic stress, targeting protein catabolism with single or combination therapies is an effective strategy in MM. In this article, we review the scientific rationale and bases for therapeutic application and effectiveness of Food and Drug Administration–approved and investigational drugs targeting protein homeostasis in MM.