Regulatory B cells (Bregs) play a significant role in immunopathological and prognostic contexts in humans. These cells are a heterogeneous group of B lymphocytes capable of suppressing inflammatory immune reactions, contributing to immune homeostasis by limiting immune responses. Bregs are involved in attenuating pathological inflammatory reactions associated with transplant rejection, graft-versus-host disease, autoimmune diseases, allergies, and various infectious, neoplastic, and metabolic conditions. Initially, Bregs were thought to be IL-10-secreting cells, but recent studies have identified other molecules, such as IL-35, TGF-β, granzyme B, and cell surface proteins like PD-L1, CD1d, and CD25, as contributing to their immunosuppressive functions. Bregs exhibit diverse phenotypic and transcriptional properties, with several subtypes, including IL-10+, GrB+, TGF-β+, and IL-35+ Bregs, each playing distinct roles in immune regulation. In inflammatory immunopathologies, Bregs are crucial for maintaining tolerance and preventing chronic inflammation and autoimmunity. Studies have shown that increased Breg frequencies are associated with tolerance in kidney transplant recipients, while reduced Breg frequencies are linked to transplant rejection. In autoimmune diseases, Bregs are often functionally impaired, and their deficiency is associated with disease progression. In infections, Bregs contribute to immune regulation by producing anti-inflammatory cytokines and modulating immune responses. In neoplastic diseases, Bregs can have both protective and immunosuppressive roles, with their presence correlating with improved clinical outcomes in some cancers but also with poor prognosis in others. Despite their importance, there are currently no clinical approaches that intentionally modulate Breg frequency or function. Research is ongoing to explore the therapeutic potential of Bregs in various diseases, with a focus on their role in immunotherapy and tolerance induction. The development of GMP-compliant manufacturing processes for Bregs is essential for translating their potential into clinical applications. Overall, Bregs represent a promising area of research in immunology, with significant implications for the treatment of various human diseases.Regulatory B cells (Bregs) play a significant role in immunopathological and prognostic contexts in humans. These cells are a heterogeneous group of B lymphocytes capable of suppressing inflammatory immune reactions, contributing to immune homeostasis by limiting immune responses. Bregs are involved in attenuating pathological inflammatory reactions associated with transplant rejection, graft-versus-host disease, autoimmune diseases, allergies, and various infectious, neoplastic, and metabolic conditions. Initially, Bregs were thought to be IL-10-secreting cells, but recent studies have identified other molecules, such as IL-35, TGF-β, granzyme B, and cell surface proteins like PD-L1, CD1d, and CD25, as contributing to their immunosuppressive functions. Bregs exhibit diverse phenotypic and transcriptional properties, with several subtypes, including IL-10+, GrB+, TGF-β+, and IL-35+ Bregs, each playing distinct roles in immune regulation. In inflammatory immunopathologies, Bregs are crucial for maintaining tolerance and preventing chronic inflammation and autoimmunity. Studies have shown that increased Breg frequencies are associated with tolerance in kidney transplant recipients, while reduced Breg frequencies are linked to transplant rejection. In autoimmune diseases, Bregs are often functionally impaired, and their deficiency is associated with disease progression. In infections, Bregs contribute to immune regulation by producing anti-inflammatory cytokines and modulating immune responses. In neoplastic diseases, Bregs can have both protective and immunosuppressive roles, with their presence correlating with improved clinical outcomes in some cancers but also with poor prognosis in others. Despite their importance, there are currently no clinical approaches that intentionally modulate Breg frequency or function. Research is ongoing to explore the therapeutic potential of Bregs in various diseases, with a focus on their role in immunotherapy and tolerance induction. The development of GMP-compliant manufacturing processes for Bregs is essential for translating their potential into clinical applications. Overall, Bregs represent a promising area of research in immunology, with significant implications for the treatment of various human diseases.