The original version of the hygiene hypothesis suggested that infections transmitted early in life by “unhygienic contact” prevented allergies. Examples were endemic fecal-oral infections by viral, bacterial, or protozoic pathogens, such as hepatitis A virus, Helicobacter pylori, or Toxoplasma gondii. Later, this concept also included microorganisms beyond pathogens, such as commensals and symbionts, and the hygiene hypothesis was extended to inflammatory diseases in general. An impressive illustration of the hygiene hypothesis was found in the consistent farm effect on asthma and allergies, which has partly been attributed to immunomodulatory properties of endotoxin as emitted by livestock. Assessment of environmental microorganisms by molecular techniques suggested an additional protective effect of microbial diversity on asthma beyond atopy. Whether microbial diversity stands for a higher probability to encounter protective clusters of microorganisms or whether it is a proxy of a balanced environmental exposure remains elusive. Diversity of the mucosal microbiome of the upper airways probably reflects an undisturbed balance of beneficial microorganisms and pathogens, such as Moraxella catarrhalis, which has been associated with subsequent development of asthma and pneumonia. In addition, specific fermenters of plant fibers, such as the genera Ruminococcus and Bacteroides, have been implied in asthma protection through production of short-chain fatty acids, volatile substances with the capability to reduce T-helper cell type 2-mediated allergic airway inflammation. Evolutionary thinking may offer a key to understanding noncommunicable inflammatory diseases as delayed adaptation to a world of fast and profound environmental changes. Better adaptation may be fostered by growing insight into the interplay between man and microbiome and an adequate choice of the environmental exposure.