The hygiene hypothesis was initially formulated to explain the steep increase in the prevalence of allergies in Western societies observed over the past few decades. It proposes that the microbial environment interfaces with the innate immune system and modulates its ability to impart instructions to adaptive immune responses, particularly when such interactions occur in utero and/or in early life. Recent research on the molecular mechanisms of the hygiene hypothesis highlights the role of Toll-like receptor ligands in modulating allergic inflammation and the importance of bacterial products in directing the development of the host's immune system. Genetic analysis, by contrast, clearly shows that the response threshold of the immune system to environmental stimuli is controlled by natural genetic variation and gene-environment interactions, suggesting that the complex interplay between the organism and the environment might not be regulated by a single mechanism.