After several decades of controversies, allergen specific immunotherapy (SIT) was recognized as an effective treatment for respiratory and hymenoptera allergy by the World Health Organization in 1998. SIT involves the administration (usually subcutaneous) of increasing doses of allergen in order to achieve a hyposensitization. Moreover, SIT is the only allergen-specific treatment capable of modifying the natural history of the disease. During the last 25 years, there was an impressive development of basic and clinical research in the field of SIT, with the goal of improving the safety, the efficacy and ameliorating the knowledge on the mechanisms of action. In this regard, the sublingual route (SLIT) was extensively studied and, recently, validated. SLIT can be considered a milestone in the history of SIT, since it is expected to change the clinical practice. In parallel, the growing detailed knowledge of the immunological mechanisms of SIT has provided the opportunity to explore new forms of specific hyposensitization, such as the use of adjuvants (bacterial and DNA-based), recombinant and engineered allergens, allergenic peptides and chimeric molecules. The last frontier seems to be the manipulation of genoma with replicons and allergen-encoding plasmids.