Substantial progress in understanding mechanisms of immune regulation in allergy, asthma, autoimmune diseases, tumors, organ transplantation and chronic infections has led to a variety of targeted therapeutic approaches. Allergen-specific immunotherapy (AIT) has been used for 100 years as a desensitizing therapy for allergic diseases and represents the potentially curative and specific way of treatment. The mechanisms by which allergen-AIT has its mechanisms of action include the very early desensitization effects, modulation of T- and B-cell responses and related antibody isotypes as well as inhibition of migration of eosinophils, basophils and mast cells to tissues and release of their mediators. Regulatory T cells (Treg) have been identified as key regulators of immunological processes in peripheral tolerance to allergens. Skewing of allergen-specific effector T cells to a regulatory phenotype appears as a key event in the development of healthy immune response to allergens and successful outcome in AIT. Naturally occurring FoxP3(+) CD4(+)CD25(+) Treg cells and inducible type 1 Treg (Tr1) cells contribute to the control of allergen-specific immune responses in several major ways, which can be summarized as suppression of dendritic cells that support the generation of effector T cells; suppression of effector Th1, Th2 and Th17 cells; suppression of allergen-specific IgE, and induction of IgG4; suppression of mast cells, basophils and eosinophils and suppression of effector T cell migration to tissues. New strategies for immune intervention will likely include targeting of the molecular mechanisms of allergen tolerance and reciprocal regulation of effector and regulatory T cell subsets.