From the era of subcutaneous immunotherapy (SCIT) in 1960s, allergen immunotherapy (AIT) has been established as a highly effective and curable treatment for allergic diseases. Furthermore, the recent appearance of sublingual immunotherapy (SLIT) in which the complicated administration procedure in SCIT was improved has been causing paradigm shifts in the treatment of allergic rhinitis. During the long history of AIT, the mechanisms by which this therapy leads its strong efficacy have been investigated but not fully clarified yet. The production of blocking antibodies that interrupt allergen-IgE binding, normalization of Th1/Th2 balance, and introduction of regulatory T cells are the major candidate mechanisms, though there are several conflicting reports. In our recent clinical study of SLIT against Japanese cedar pollinosis, we also tried to elucidate its mechanisms. Especially by comparing high-responder and non-responder patients using integrated analysis with multiple data, not by comparing with a placebo control group using individual data, we have successfully identified several target molecules and cascades of SLIT. Herein, we would like to describe the potential mechanisms by which AIT exhibits its strong efficacy with referring our recent novel findings.