Allergen immunotherapy (AIT) is still the only available therapy for allergic diseases that acts on the immune dysfunction underlying the allergy and can modify the course and progression of the disease. The modern principle of immunotherapy is not significantly different from the idea that Leonard Noon had in 1911, when AIT was first used for the treatment of allergic rhinitis. AIT implies repeated application of increasing doses of allergen by subcutaneous injections up to a maintenance dose that is administered for at least three years, which achieves specific tolerance to the allergen with long-term efficacy even after treatment discontinuation. More recently, the sublingual route of administration, which can be carried out at home, has proven to be an effective and safe alternative to the subcutaneous route. Oral immunotherapy is increasingly used in the treatment of IgE-mediated food allergy and enables the achievement of effective limited desensitization, but not long-term tolerance. Immunological mechanisms of tolerance include increased production of interleukin 10 (IL-10) and transforming growth factor beta (TGF-β), reduction in the number of allergen-specific T helper cells type 2 (Th2), induction of allergen-specific regulatory T and B lymphocytes (Tregs and Bregs) and the production of allergenspecific IgG4 and IgA blocking antibodies. Considering the continuous increase in the prevalence of allergic diseases, it is of great interest in the treatment of allergies to investigate new methods for achieving immunotolerance with a safer, more effective and long-lasting effect; these include alternative routes of administration of allergens for immunotherapy, new adjuvants, recombinant allergens (including hypoallergenic variants), and the combination of allergens with immune modifiers or monoclonal antibodies that suppress the Th2 cell pathway.