Studies have shown that endotoxin exposure in childhood is associated with a reduced risk of atopy and atopic asthma. It is commonly assumed that these effects only occur in early life. However, recent epidemiologic studies suggest that immune deviation might take place throughout life. Assuming that the immune system is not fixed after the first years of life, we hypothesize that endotoxin exposure might not only inhibit the development of atopic sensitization and disease at any time throughout life but might also reverse this process. This novel extension of the hygiene hypothesis is primarily based on the indirect evidence of several epidemiologic observations showing a reduction in atopy in adults highly exposed to endotoxin that is unlikely to be explained by protective effects alone. In addition, some animal studies demonstrated the potential of endotoxin to downregulate pre-existing airway eosinophilia and hyperreactivity. However, there is currently little direct evidence that endotoxin might reverse atopy and allergic diseases. Observational studies and randomized trials to test this hypothesis could ultimately lead to the development of novel treatments for atopic diseases, such as allergic asthma, hay fever, and eczema.