Specific immunotherapy (SIT) is widely used for treatment of allergic diseases and could potentially be applied in other immunological disorders. Induction of specific unresponsiveness (anergy) in peripheral T cells and recovery by cytokines from the tissue microenvironment represent two key steps in SIT with whole allergen or antigenic T cell peptides (PIT). The anergy is directed against the T cell epitopes of the respective antigen and characterized by suppressed proliferative and cytokine responses. It is initiated by autocrine action of IL‐10, which is increasingly produced by the antigen‐specific T cells. Later in therapy, B cells and monocytes also produce IL‐10. The anergic T cells can be reactivated by different cytokines. Whereas IL‐15 and IL‐2 generate Th1 cytokine profile and an IgG4 antibody response, IL‐4 reactivates a Th2 cytokine pattern and IgE antibodies. Increased IL‐10 suppresses IgE and enhances IgG4 synthesis, resulting in a decreased antigen‐specific IgE:IgG4 ratio, as observed normally in patients after SIT or PIT. The same state of anergy against the major bee venom allergen, phospholipase A₂, can be observed in subjects naturally anergized after multiple bee stings. Together, these data demonstrate the pivotal role of autocrine IL‐10 in induction of specific T cell anergy and the important participation of the cytokine microenvironment in SIT. Furthermore, knowledge of the mechanisms explaining reasons for success or failure of SIT may enable possible predictive measures of the treatment.—Akdis, C. A., Blaser, K. IL‐10‐induced anergy in peripheral T cell and reactivation by microenvironmental cytokines: two key steps in specific immunotherapy. FASEB J. 13, 603–609 (1999)