Tumor necrosis factor-alpha (TNF) is a pleiotropic cytokine, which is thought to play a major role in the pathogenesis of inflammatory diseases, including allergy. TNF is produced at the early stage of allergen sensitization, and then continues to promote the inflammation cascade in the effector phase of allergic reactions. Consequently, anti-TNF treatment has been proposed as a potential therapeutic option. However, recent studies reveal anti-intuitive effects of TNF in the activation and proliferative expansion of immunosuppressive Tregs, tolerogenic DCs and MDSCs. This immunosuppressive effect of TNF is mediated by TNFR2, which is preferentially expressed by immunosuppressive cells. These findings redefine the role of TNF in allergic reaction, and suggest that targeting TNF-TNFR2 interaction itself may represent a novel strategy in the treatment of allergy. Highlights-Pleiotropic function of TNF in allergy is likely mediated by its two receptors, TNFR1 and TNFR2-Activation by TNFR1 results in the allergic inflammatory responses while TNFR2 plays a role in the immune tolerance to allergens-TNFR2 is preferentially expressed by highly suppressive and replicating Tregs and TNFR2 signaling leads to the activation and proliferation of Tregs-Targeting of TNFR2 to boost Treg activity may represent a novel strategy for treating patients with allergy.