Sexually transmitted viral infections (STIs) are often not naturally controlled, and it is widely accepted that vaccines against STIs need to achieve a response superior to the one elicited by natural infections. CD8 T-cells can play a critical role in controlling STIs, but the parameters required for eliciting protective CD8-mediated immune response is not well understood. This critical gap in our understanding of the requirements for generating a successful antiviral CD8 T-cell response in the tolerogenic environment of the female reproductive tract (FRT) must be fulfilled before innovative vaccine strategies against STIs can be envisioned. To date, we have lacked a small-animal model to study how protective CD8 T-cell immunity develops against vaginally transmitted viral pathogens, in particular RNA viruses. In the past several years, we have directed our efforts and focus towards developing a mouse model of genital infection using LCMV. Using this infection model, we have begun to better understand the magnitude, kinetics, and type of CD8 T-cell response generated after vaginal LCMV transmission as compared to those generated during systemic infection. We are also intensely focusing on the complex interactions among innate immune cells that regulate and fine-tune the right amount and type of CD8 T-cell response against mucosally transmitted LCMV, which is crucial for controlling the virus without causing immunopathogy. Thus, our research focuses on how to achieve T-cell-mediated protective immunity in the genital mucosa, which will ultimately support the development of successful vaccines against sexually transmitted infections, in particular RNA viruses, such as HIV.