The prevalence and severity of allergic diseases and other diseases of immune dysregulation are increasing in industrialized countries. One explanation for these trends is that decreased exposure to microbes, due to modern public health practices, has resulted in the loss of a main source of immune provocation, and a consequent increase in pathogenic immune responses and their associated diseases. It is now clear that molecular interactions between immunocytes and microbes are mediated largely by Toll-like receptors (TLRs) on host cells and a diversity of ligands produced by viruses, bacteria and fungi. Physiological exposures to TLR ligands are also likely to have an important yet complex role in host immune homeostasis and predisposition towards atopy.