Allergen-specific immunotherapy (IT) is the only treatment of allergy in adults and children capable of modifying the immune response at early steps. As a consequence, IT improves symptoms, prevents the onset of new sensitizations, reduces the risk of developing asthma and its clinical efficacy lasts many years. The main rationale for administering sublingually IT (SLIT) is to reduce the occurrence of side effects, still yet preserving the immunological effects. SLIT with the most common allergens have been used in many studies with significant clinical effectiveness in both asthma and rhinitis. The pharmacokinetic of allergens administered through non injection routes is complex. Peptide absorption across oral mucosa occurs mainly by passive diffusion but delivery of proteins has some limitations. Moreover, the molecular mechanisms responsible for the efficacy of SLIT are poorly defined. In this review we focus on the anatomy/histology of the oral cavity as well as on the associated immunological structures to envisage what may happen when an allergen is kept in the mouth. Moreover, the induction of immune responses in this particular immunological environment is also discussed.