Simple Summary: The implantation of proteasome inhibitors was a milestone in the treatment of multiple myeloma (MM). One such first-in-class molecule was bortezomib (BTZ). Its cytotoxic effects are exerted through proteasome inhibition and the subsequent accumulation of misfolded or otherwise defective proteins. In addition to its main mechanisms of action, BTZ elicits various epigenetic alterations within target cells which are part of its mechanism of action. Importantly, epigenetic changes also participate in mediating resistance to BTZ. Some epigenetic agents such as azacitidine act synergically with BTZ or have the potential to restore sensitivity to the drug in resistant malignant cells. In this paper, we reviewed the epigenetic aspects of BTZ molecular action with a particular emphasis on drug resistance mechanisms and potential clinical implications. Bortezomib (BTZ) is widely implemented in the treatment of multiple myeloma (MM). Its main mechanism of action is very well established. BTZ selectively and reversibly inhibits the 26S proteasome. More precisely, it interacts with the chymotryptic site of the 20S proteasome and therefore inhibits the degradation of proteins. This results in the intracellular accumulation of misfolded or otherwise defective proteins leading to growth inhibition and apoptosis. As well as interfering with the ubiquitin–proteasome complex, BTZ elicits various epigenetic alterations which contribute to its cytotoxic effects as well as to the development of BTZ resistance. In this review, we summarized the epigenetic alterations elicited by BTZ. We focused on modifications contributing to the mechanism of action, those mediating drug-resistance development, and epigenetic changes promoting the occurrence of peripheral neuropathy. In addition, there are therapeutic strategies which are specifically designed to target epigenetic changes. Herein, we also reviewed epigenetic agents which might enhance BTZ-related cytotoxicity or restore the sensitivity to BTZ of resistant clones. Finally, we highlighted putative future perspectives regarding the role of targeting epigenetic changes in patients exposed to BTZ. [ABSTRACT FROM AUTHOR]