Allergen immunotherapy (AIT) has proven efficacy in IgE-dependent respiratory diseases. When AIT is conducted continnuosly for 3 years, it confers long-term clinical benefits after cessation of treatment. While multiple studies confirm high efficacy of AIT, there are some patients who do not respond to this therapy (“non-responders”) or find its results non-satisfactory (“poor-responders”). What factors may be responsible for lack of a therapeutic success of AIT or the therapy’s not fully optimal result? How to predict AIT treatment failures? Can biomarkers facilitate the prediction? How to identify patients who may turn out to be treatment failures? The article sets forth causes of AIT failures: wrong diagnosis of the underlying allergic disease, selection of a clinically non-important allergen for AIT, lack of sensibilization to the major allergen and badly performed AIT. In regard to AIT success of failure, additionally addressed is the issue of heterogeneity of molecular profiles and the sensibilization to clinically important molecules like Der p 23.