The Toll-like receptors (TLRs) are innate sensors that recognize both microbial and endogenous ligands, initiating the host defense response. TLRs initiate the potent proinflammatory response to infection, are the target for adjuvants, and are essential for the establishment and maturation of adaptive immunity. As such they have been the interest of widespread research and the target of therapeutic intervention on multiple diseases. It has become apparent that expression of a subset of TLRs (TLR1, TLR2, TLR3, TLR5, and TLR7) is induced by Type I interferons (IFN). The role and impact of IFN expression on TLR responses is therefore critical in understanding the role of TLRs in disease, particularly as IFN itself is a downstream gene induced by specific TLRs. In this review we discuss the function and role of IFN-regulated TLRs in disease and how the role of IFN may impact upon TLR induction of the immune response in diseases, particularly in mouse models.