In recent years, it has become increasingly evident that mammalian Toll-like receptors (TLRs) play a critical role in determining the outcome of virus infection. TLRs have evolved to recognize viral nucleic acids, and promote the stimulation of innate and adaptive immune responses. Interestingly, the study of mice harboring deficiencies in various TLR proteins and their adaptors suggests that TLR activation promotes protective anti-viral immunity in some cases, while exacerbating virus-induced disease in others. In this report we describe the interactions of viruses with both the TLR system and the intracellular recognition system and highlight the role of TLRs in shaping the outcome of virus infection in both a positive and negative manner.