Innate responses to microbes are mediated in large part via toll-like receptors (TLRs) that recognize a diverse family of ligands produced by viruses, bacteria, and fungi. Great effort has been directed toward translating this knowledge into the development of therapies for the prevention and treatment of diseases, including those fueled by allergic (Th2-biased) hypersensitivities. In this review, we consider the ways in which ligands for different TLRs influence the allergic phenotype. In addition, an update on safety and efficacy data from clinical trials of allergic patients treated with TLR9 ligand-based interventions is provided. Finally, recent experimental results that help elucidate how ambient TLR ligand exposures influence allergic risk and their relevance to the development of TLR ligand-based therapeutics are discussed. Investigations presented within this opinion paper suggest that several TLR ligands could have clinical utility in the treatment of allergic diseases, whereas other TLR ligands appear less attractive, as they facilitate development of Th2-biased hypersensitivities in murine studies.