Humoral immunity is a critical component of the adaptive immune system and provides protection through the generation of antibodies. In the context of disease, plasma cells that are malignant, self-reactive, or alloreactive in transplantation, can be detrimental to the health of the host. Although proteasome inhibition entered the clinic with substantial success over 2 decades ago, resistance to therapy develops in most settings and improvements on this life-saving therapy may be enhanced by understanding its mechanisms of action. In Chapter 2, we identified a mechanism of action in early activated B cells that is mediated by the tumor suppressor p53 in response to BTZ. Furthermore, p53 potentiation at proliferative stages of B cell differentiation was able to promote apoptosis, further implicating its activity in BTZ-induced apoptosis. Finally, we found that inhibition of the E3-ligases MDM2 and the APC/C with nutlin3a and proTAME, respectively, was sufficient to induce apoptosis and prevent B cell differentiation into plasma cells. In Chapter 3, we identified a preferential reduction of newly-formed plasma cells over their longer-lived counterparts in response to BTZ treatment. We found that acute doses of BTZ depleted most plasma cells with a small surviving population of cells with a B220- Bim- phenotype, suggesting that upstream regulators of Bim activity might be involved in BTZ-induced cell death. To that point, we tested the role of the transcription factor CHOP in mediating BTZ-induced cell death in plasma cells and identified a modest rescue effect. Collectively, these studies provide novel insights into the mechanisms of action of BTZ-induced cell death in B lineage cells at multiple stages of differentiation.