The possibility that the hygiene hypothesis is the most reasonable explanation for the increased prevalence of both allergy (in which the immune response is dominated by Th2 cells) and Th1-mediated autoimmunity is supported by the observations that exposure of humans to microbial agents in early life can exert protection against these disorders later. However, there still remains a question about how environmental microbes can decrease both Th1 and Th2 immune-mediated disorders, the two opposite spectrums of the immune responses. Cytokines are considered the main determining factors in the initial differentiation of T cells to Th1 and Th2 subsets. IL-18 as a multifunctional cytokine is capable of polarizing the immune response to both of these distinct subsets depending on the genetic background and cytokine milieu. It is hypothesized that the reduced exposure to microbial agents in early life leads to the aberrant production of IL-18, which in turn influences individuals quite differently depending on their genetic background. In genetically predisposed individuals to allergy, it augments Th2 responses and in genetically predisposed individuals to Th1-autoimmunity it accelerates Th1 responses.