Allergic disease prevalence rates have increased dramatically in affluent countries over the last half century. One proposed explanation is that decreased exposures to microbes caused by modern public health practices has led to deficiencies in an important source of immune education and a consequent increase in the risk of pathogenic immune responses to environmental antigens. Recently, it has become clear that innate responses to microbes are mediated in large part by Toll-like receptors (TLRs), which recognize a diverse family of ligands produced by viruses, bacteria, and fungi. In this perspectives article we will review experimental evidence suggesting that TLRs also play a dominant role in innate responses to noninfectious immunostimulatory materials present in environments of daily living. We will further discuss how ligands for different TLRs can polarize the TH bias of adaptive responses in opposing directions. Finally, we will consider how TLRs might contribute to the genesis of atopy and the clinical potential of pharmacologic interventions that target TLRs for the prevention and treatment of allergic diseases.