House dust mite (HDM) is the most significant indoor allergen, responsible for not only many cases of rhinoconjunctivitis but also for many cases of bronchial asthma, rendering it of considerable socioeconomic relevance. Besides symptomatic treatment and avoidance measures, allergen immunotherapy (AIT) is crucial, as the only causal, disease-modifying therapeutic approach. However, high diagnostic certainty is essential for initiating AIT. The challenge in making a correct diagnosis lies in interpreting the demonstrated HDM sensitization regarding its clinical relevance (clinically silent sensitization vs. allergy). While the risk of allergy increases with the level of IgE titers against HDM extract, Der p 1, or Der p 2, as well as with the breadth of the molecular sensitization profile against HDM components (Der p 1, Der p 2, Der p 23), no threshold can be defined for the presence of allergy, nor can sensitization to a specific component be confidently considered allergy inducing. It should be noted that at least in Southern Bavaria, the prevalence of Der p 23 sensitization is too low to be considered a major allergen, and Der p 23 is not able to molecularly differentiate all HDM sensitizations when added to the two major allergens Der p 1 and Der p 2. Evidently, HDM possesses a diverse profile of allergens, with some relevant ones possibly yet to be described. Unfortunately, patient history does not provide a sufficient assessment of the clinical relevance of a demonstrated HDM sensitization, necessitating allergen provocation testing before initiating AIT with HDM, despite the relatively large effort involved.