The hygiene hypothesis of atopic disease suggests that environmental changes in the industrialized world have lead to reduced microbial contact at an early age and thus resulted in the growing epidemic of atopic eczema, allergic rhinoconjunctivitis, and asthma. The epidemiological findings have been combined with the Th1/Th2 paradigm of immune responsiveness to provide a coherent theory. Recent advances in epidemiology and immunology demonstrate, however, that the hygiene hypothesis may need to be extended in three respects. First, the importance of infections in causing immune deviance may be outweighed by other sources of microbial stimulation, perhaps most importantly by the indigenous intestinal microbiota. Second, immunomodulatory and suppressive immune responses complement the Th1/Th2 paradigm. Third, in addition to protection against atopy, protection against infectious, inflammatory, and autoimmune diseases may also depend upon healthy host-microbe interactions implicated in the hygiene hypothesis.