Causes explaining the epidemic of IgE-associated (allergic) diseases are unclear. MeDALL (Mechanisms of the Development of Allergy) aims at generating novel knowledge on mechanisms of allergy initiation, in particular in childhood. To understand how a complex network of genetic and environmental factors leads to complex allergic phenotypes, a novel stepwise, large and integrative translational approach is needed. MeDALL includes experts in allergy, epidemiology, genetics, immunology, biology, animal models, biochemistry and systems biology combining strengths of ongoing EU projects. Classical phenotypes (expert-based) and novel phenotypes of allergy (hypothesis-free statistical modelling) are compared. Population-based data are collected from a cross-sectional study (Karelia) and existing birth-cohorts followed using a common protocol. IgE to foods and inhalants are tested using component-resolved diagnosis across Europe in populations. Biomarker profiles (“fingerprints”) are extensively assessed using epigenetics, targeted proteomics and unbiased transcriptomics in a subsample of the study population. Those associated with allergic phenotypes are validated in large study populations. Relevant fingerprints are combined into network biomarker phenotype “handprints” using a systems biology approach and validated in a sufficiently powered sample. Animal studies and in vitro human immunology reinforce the validation. This information coupled with classical and novel phenotypes characterize environmental protective and susceptibility factors of allergy and risk groups. Results are fitted into new integrative complex mathematical models to establish suitable biomarkers for early diagnosis, prevention and targets for therapy of allergy-associated diseases such as asthma and atopic dermatitis. Ethics and gender are considered. MeDALL aims at improving health of European citizens, Europe competitiveness and innovative capacity while addressing global health issues.