I discuss herein our efforts to identify biological markers of efficacy in support of the development of sublingual allergy vaccines. Biomarkers are of major interest to facilitate clinical development, for example by predicting safety and efficacy of candidate vaccines or their components (e.g. adjuvants and formulations) on the basis of immunogenicity evaluated in humans. They will be mandatory in the future to evaluate customized recombinant allergy vaccines designed upon component-resolved diagnosis. In this regard, they must ideally be both qualitative and quantitative. Such markers would also be useful to confirm foreseen mechanisms of action potentially associated with successful immunotherapy (e.g. the Treg hypothesis). The recent availability of sophisticated technologies (referred here as the technology push) to assess in details both humoral and cellular arms of the immune system provides new opportunities to identify such markers. In this regard, documenting natural immune responses, most particularly allergen-specific T cell responses in healthy persons, is critical to identify immunological correlates of protection, and thus to design optimal allergy vaccines.