Most indigenous microbes occur in the intestinal tract, and their interactions with the host are largely unknown. Current understanding of host-microbe interactions links early microbial contact to the origin of disease, a theory that has its roots in the hygiene hypothesis. Modern life style appears to deprive the infant of conditions that provide adequate anti-inflammatory or tolerogenic stimuli upon antigen encounter. Thus, maturational signals from the environment and the diet are insufficient to adequately shape the immune system. This publication deals with the relationship between the gut microbiota as well as altered pattern of early microbial contact and the origin of human disease. New aspects of the original hygiene hypothesis are discussed in relation to disorders spanning from allergy and autoimmunity to obesity.The results presented suggest that all these disorders may be linked to aberrant antigen absorption and immune responses associated with dysfunction of mucosal defense. Researchers, clinicians and students interested in the interaction of the host with indigenous gut bacteria and the consequences for human health will find this publication of utmost interest.