Allergen immunotherapy (AIT) has been in use since more than one century, when Leonard Noon experimentally proved its efficacy in hayfever (Noon, in Lancet 1: 1572-3, 1911). Since then, AIT was administered only as subcutaneous injections (SCIT) until the sublingual route (SLIT) was proposed in 1986. The use of SLIT was proposed following several surveys from the USA and UK that repeatedly reported fatalities due to SCIT (Lockey et al. in J Allergy Clin Immunol 75(1): 166, 1985; Lockey et al. in J Allergy Clin Immunol 660-77, 1985; Committee on the safety of medicines. CSM update. Desensitizing vaccines. Br Med J, 293: 948, 1986). These reports raised serious concerns about the safety and the risk/benefit ratio of AIT. Many cases of life-threatening events with SCIT were due to avoidable human errors in administration, but a relevant fraction of them remained unexplained and unpredictable (Aaronson and Gandhi in J Allergy Clin Immunol 113: 111721, 2014). Subsequently, in a few years, SLIT gained credibility and was included in the official documents and guidelines (Table 1) (Bousquet et al. in J Allergy Clin Immunol 108(5 Supp): S146-S150, 2001; Canonica et al. in Allergy 64 (Supp 91): 1-59, 2009) as a viable alternative to traditional SCIT. Of note, the local bronchial (aerosol) and the intranasal route of administration were attempted after the 1970s as alternatives to SCIT: the bronchial route was soon abandoned due to the poor efficacy and/or side effects, and the local nasal route, although effective and safe, was judged substantially impractical (Canonica and Passalacqua in J Allergy Clin Immunol 111: 437-48, 2003). In contrast to SCIT, SLIT was tested in very large clinical trials (need references), including hundreds of patients and with dose-ranging experimental designs, so that some products (tablets) for grass, mite, and ragweed were officially approved as commercial drugs by regulatory agencies such as the Food and Drug Administration and the European Medicines Agency and the optimal content for the maintenance dose was identified for selected allergens. In parallel, the knowledge on the mechanisms of action of AIT was rapidly refined, leading to further improvements, such as the chemically modified extracts and the use of adjuvants to enhance efficacy and safety. In addition, in the last 10 years, there has been an increasing scientific and clinical interest in AIT applied to food allergies, in particular in children, with the use of orally administered extracts (Albin and Nowak-Wegrzyn in Immunol Allergy Clin North Am 35: 77-100, 2015). The results are so far encouraging, at least for cow's milk, egg, and peanut, although the use of treatment is still restricted to clinical trials or within specialized centers. Finally, the introduction of molecular-or component-resolved diagnosis has allowed detailing the prescription of AIT, by better delineating true sensitization versus cross-reactivity (Canonica et al. in World Allergy Organ J 6(1): 17, 2013). This latter point is also in strict relation to the use of recombinant, engineered or highly purified molecules, instead of raw extracts, for the desensitization process.