B cells critically contribute to health through the production of antibodies that provide a vital line of defence against infectious agents. In addition, B cells are known to play an integrative role in immunity, acting as crucial antigen-presenting cells for T cells, and being an important source of cytokines that can target multiple cell types including stromal cells, innate cells, and adaptive lymphocytes. This review focuses on the role of B cells as negative regulators of immunity through the production of interleukin-10 (IL-10) in autoimmune, infectious, and malignant diseases. It discusses the phenotypes of the B cell subsets most competent to produce IL-10 in vitro and to exert suppressive functions in vivo upon adoptive transfer in recipient mice, the signals and transcription factors regulating IL-10 expression in B cells, and the recent identification of plasmocytes, including short-lived plasmablasts and long-lived plasma cells, as an important source of IL-10 in secondary lymphoid organs and inflamed tissues in vivo during mouse and human diseases. With our increasing knowledge of this non-canonical B cell function a coherent framework starts emerging that will help monitoring and targeting this B cell function in health and disease.