Plasma cells (PCs) are the major source of pathogenic allo‐ and autoantibodies and have historically demonstrated resistance to therapeutic targeting. However, significant recent clinical progress has been made with the use of second‐generation proteasome inhibitors (PIs). PIs provide efficient elimination of plasmablast‐mediated humoral responses; however, long‐lived bone marrow (BM) resident PCs (LLPCs) demonstrate therapeutic resistance, particularly to first‐generation PIs. In addition, durability of antibody (Ab) reduction still requires improvement. More recent clinical trials have focused on conditions mediated by LLPCs and have included mechanistic studies of LLPCs from PI‐treated patients. A recent clinical trial of carfilzomib (a second‐generation irreversible PI) demonstrated improved efficacy in eliminating BM PCs and reducing anti‐HLA Abs in chronically HLA‐sensitized patients; however, Ab rebound was observed over several weeks to months following PI therapy. Importantly, recent murine studies have provided substantial insights into PC biology, thereby further enhancing our understanding of PC populations. It is now clear that BMPC populations, where LLPCs are thought to primarily reside, are heterogeneous and have distinct gene expression, metabolic, and survival signatures that enable identification and characterization of PC subsets. This review highlights recent advances in PC biology and clinical trials in transplant populations. Recent application of powerful new investigative tools are beginning to reveal previously unrecognized aspects of the biology of plasma cells, thereby identifying promising new approaches for enhancing current targeting strategies.