- Control of virus replication initially depends on rapid activation of the innate immune responses. Toll-like receptor (TLR) ligands are potent inducers of innate immunity against viral infections, including herpes simplex virus (HSV). HSV-2 is currently one of the most common sexually transmitted infections in developed nations and is becoming more prevalent in adolescents. HSV-2 infects the genital mucosa and is associated with an increased risk of obtaining other sexually transmitted infections such as HIV. There is currently no vaccine available against HSV-2. In the last several years, there has been an interest in utilizing Toll-like receptor (TLR) ligands to initiate innate immune responses in order to provide an early line of defence against viral replication. This review highlights recent studies investigating the effect of various TLR ligands on genital HSV-2 infection. A considerable body of information has been published on the effect of local delivery of TLR ligands on HSV-2 replication in genital mucosa. We have outlined ligands that have a potential to provide protection against HSV-2 infection. In addition, we have presented possible mechanisms by which the local delivery of TLR ligands provides innate protection against genital HSV-2.