In the last few years strong evidence has accumulated to suggest that allergen-reactive type-2 T helper (T_H2) cells play an important role in the induction and maintenance of the allergic inflammatory cascade. First, cytokines and chemokines produced by T_H2 cells (GM-CSF, IL-4, IL-5, IL-6, IL-9, IL-10, IL-13, macrophage-derived chemokine) and those produced by other cell types in response to T_H2 cytokines or as a reaction to T_H2-related tissue damage (eotaxin, transforming growth factor-β, IL-11) account for most pathophysiologic aspects of allergic disorders (production of IgE antibodies; recruitment or activation of mast cells, basophils, and eosinophils; mucus hypersecretion; subepithelial fibrosis; and tissue remodeling). The T_H2 hypothesis may also explain the complex genetic background responsible for allergic disorders. Several genes are involved in the development and regulation of T_H2 cells and may provide the reason why the prevalence of atopic allergy is increasing in Western countries. Indeed, a dramatic change has occurred in the last several decades in the “microbial” environment of children, thus probably altering the balance between T_H1 and T_H2 responses to “innocuous” antigens (allergens) in favor of T_H2 responses. Finally, the T_H2 hypothesis offers exciting opportunities for the development of novel immunotherapeutic strategies targeted to address allergen-specific T_H2 cells or T_H2-derived effector molecules in atopic individuals. (J Allergy Clin Immunol 2000;105:399-408.)