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Abstract Diagnostic tests to detect allergic sensitization were introduced at the end of the nineteenth century but only in the late 1990s did the advent of molecular allergology revolutionize the approach to the allergic patient. Personalized Medicine, a medical procedure that separates patients into different groups with different medical decisions, practices and interventions has sanctioned this change. In fact, in the last few years molecular allergology and the observation that not every patient has the same allergic profile, even when allergic to the same allergenic source, has originated the concept “one size does not fit all”. This new approach requires the identification of still unknown allergens, but also the more detailed investigation of those already known. In depth studies of the structure–function relationships in allergenic molecules can reveal the structural determinants involved in the IgE-binding. Then, the knowledge of the epitope profile of each allergen and of the environmental/experimental conditions affecting the exposure of IgE-binding epitopes can provide important contributions to the understanding of cross-reaction processes and to the improvement of diagnosis, immunotherapy and the overall patient treatment. The evolution of diagnostic systems cannot ignore these new needs in this field.