Hydrolyzed formula feeding, delayed introduction of solid food, indoor allergen avoidance, smoke and pollutants avoidance have been applied for several decades as primary preventive measures for allergic diseases. Unfortunately, some of these strategies have had no or modest success. Therefore, resources need to be focused on better understanding of the early allergic events and on interventional studies to investigate new strategies of primary and secondary prevention. Accordingly, this review summarizes the state-of-the-art of genetic, immunological and clinical aspects of primary prevention of allergic diseases. Studies investigating gene-by-gene and gene-by-environment interactions suggest that prevention of allergic diseases must be tailored to the individual genetic susceptibilities ('gene profiling') and environmental exposures. The expanding knowledge on new T cell populations (Th17, TSLP (thymic stromal derived lymphopoietin)-dependent 'inflammatory Th2 cells') is also inspiring new concepts on the origins of allergic diseases. The old concept of 'blocking immunoglobulin G antibodies' has been re-appraised and it is likely to generate novel preventive and therapeutic strategies. The major task for future clinical research is to clearly define the timing of optimal exposure to potential allergens. In addition, the role of microbial products such as certain bacteria, or their components, and of helminths or their larvae at different times in early life, alone or with potential allergens, definitely need to be further investigated. The benefit of efficient allergy prevention, based on focusing resources on novel and promising research lines, will be of prime importance to both affluent countries and other parts of the world where allergy is only currently emerging.