A common feature between cancer escape and autoimmune diseases is an inappropriate involvement of the regulatory immune system, albeit for opposing purposes. While autoimmune disease is a reflection of the failure to control responses to self, cancer is a result of an exaggerated use of these controls to abrogate antitumor effector responses. Although the importance of regulatory B cells [Bregs, the definition first used by Mizoguchi to describe B cells exerting protection from colitis in mice (Mizoguchi et al., 1997)] in protection from autoimmunity is now accepted, their involvement in cancer escape remains poorly understood. The conundrum of Bregs is that, if their numbers are low (in analogy with Tregs), their existence and importance may be concealed by the overwhelming response of effector B cells. For example, aberrant activation of B cells promotes autoimmune diseases, such as rheumatoid arthritis (RA), type 1 diabetes mellitus (T1D), multiple sclerosis (MS), and systemic lupus erythematosus (SLE). As such, the depletion of B cells with anti-CD20 antibody rituximab impairs antigen-specific CD4+ T cell activation (Bouaziz et al., 2007) and ameliorates RA, MS, and T1D (Townsend et al., 2010). Yet, treatment with rituximab can also exacerbate the disease in some patients with ulcerative colitis, or even induce other diseases, such as psoriasis with psoriatic arthropathy and colitis in patients with Graves disease and non-Hodgkin lymphoma, respectively (Dass et al., 2007; Goetz et al., 2007; Mielke et al., 2008). The increased numbers of B cells in peripheral blood of transplant patients is positively associated with a rare but long-term drug-free clinical tolerance (Newell et al., 2010; Pallier et al., 2010; Sagoo et al., 2010). Although these clinical examples clearly indicate the importance of B cells, a current issue is how to segregate the role of Bregs from suppressive activity of B cells that has been known for more than 30 years. As first proposed by Morris and Moller in late 1960s (Morris and Moller, 1968), B cell-produced immunoglobulin can elicit immune suppression by directly triggering ITIM-mediated suppressive signaling in target cells upon binding with inhibitory FcγRIIB (Ravetch and Bolland, 2001) or by indirectly modulating dendritic cells (DCs) via activating FcγR (Morris and Moller, 1968).