An allergen is a type of protein capable of instructing the immune system to start producing IgE antibodies. The main purpose for determining the structure of major allergens is to analyze the exposed surface areas and to map the conformational epitopes. These can be determined by experimental methods including crystallographic and NMR-based approaches or predicted by computational methods. Members of the same protein family may share IgE and T cell epitopes, which can cause allergic reactions by cross-reactivity. In the clinical practice, IgE epitopes shared between inhalant and food allergens can induce an immediate IgE-mediated reaction confined to the oral cavity, known as the oral allergy syndrome. Although several structural and functional properties have been identified that contribute to allergenicity, there is not a single common denominator. Allergic sensitization, a multifactorial process, is influenced by a protein’s biological and molecular features and by its interaction pathway/s with the immune system. The innate immune system plays a fundamental role in shaping the response to potentially allergenic proteins. In this review, allergenic components of house dust mite that lead to activation of the innate immune system will be discussed as well as how allergen extracts and genes lead to allergen-induced airway inflammation. Understanding the role of mite allergen-induced innate immunity will facilitate the development of therapeutic strategies that exploit innate immunity receptors and associated signaling pathways for the treatment of allergic asthma.