Immune tolerance to both self-antigens and innocuous non–self-antigens is essential to protect the host against chronic inflammatory diseases and tissue damage. A wide range of cell types and suppressive molecules are involved in induction and maintenance of tolerance. In addition to their key function in the production of immunoglobulins, B cells can regulate immune responses through their surface molecules and secretion of cytokines. Regulatory B (Breg) cells are characterized by their immunosuppressive capacity, which is often mediated through IL-10 secretion. However, IL-35 and TGF-β have also been associated with B cell–mediated immunosuppression. Several types of murine and human Breg cells have been described, such as mouse CD5+ CD1dhi B10 cells, CD21hi CD23hi CD24hi transitional stage 2–like B cells, and CD138+ plasma cells and plasmablasts. Human Breg cell types include CD27+ CD24high B10 cells, CD24hi CD38hi immature transitional B cells, and CD73− CD25+ CD71+ BR 1 cells and a subset of plasma cells. Support for the in vivo existence of allergen-specific human Breg cells comes from direct detection of their increase during the course of allergen-specific immunotherapy, as well as their increased expression in nonallergic but high-dose allergen–exposed beekeepers. Human BR 1 cells selectively upregulate IgG4 antibodies on differentiation to plasma cells. This suggests an additional immune regulatory role because of the noninflammatory and blocking antibody function of IgG4 . Taken together, Breg cells appear to be involved in mediating allergen tolerance, but many open questions remain to be answered.