The human immune system is inseparably bonded to an individual’s personal micro-biome from birth to death. Since the beginning of life, commensal relationships have ensured the survival of micro- and macro-organisms within complex relationships. However, technological advances and altered lifestyle imposed new rules for this interaction during recent decades. It has been observed that reduced exposure to micro-organisms and parasites results in decreased morbidity and mortality, but is also associated with a rising prevalence of atopic disorders and autoimmune diseases, mostly in industrialized countries. This inverse relationship is described by the ‘hygiene hypothesis’, put forward in 1989, yet this term only imperfectly describes these observations, as excessive hygiene or hygienic measures may not directly be the central cause. The lack of appropriate immune stimulation during early childhood with the consequence of disturbed alignment in the sequence of encountering self- or non-self-antigens might account in the rise of atopy and autoimmune disease. For this reason we propose the term ‘early immune challenge hypothesis’. This concept highlights the importance of immune priming in early life in the context of genetic, social, geographic, cultural, and economic background. Moreover, it emphasizes the central role of ‘training’ of regulatory T-cells through sufficient microbial exposure, leading to a robust, healthy balance between inflammation and anti-inflammation or immune tolerance. Insufficient exposure might result in abnormal immune regulatory development. Finally, it incorporates the idea of encountering ‘old friends’ organisms that shaped our immune system during human phylogeny. This article gives a comprehensive overview of the relationship between microbial exposure, and the incidence of asthma and hay fever is outlined. Although the outcomes of these studies originally were interpreted in the framework of the hygiene hypothesis, they may suit the concept of the hypothesis of early immune challenge even better. Moreover, recent studies have revealed that TH or TReg imbalances in disease may be partially corrected by the administration of helminthic or bacterial extracts.