Chlamydia trachomatis is a Gram-negative obligate intracellular pathogen that remains the leading cause of bacterial sexually transmitted disease worldwide, despite the availability of efficacious antimicrobial therapy. Given that chlamydial infections cause severe pathological sequelae in the upper genital tract, a licensed vaccine to prevent infection and disease would be an ideal solution. Chlamydial protease-like activity factor (CPAF) is a protein secreted in considerable amounts into the cytosol of infected cells and released into the extracellular milieu upon cellular lysis, which therefore is accessible to the host immune system. This is further substantiated by the observation that CPAF is immunodominant among other antigens in Chlamydia sero-positive humans. The efficacy of vaccination with CPAF against genital chlamydial challenge has been evaluated extensively in the murine model. This review will discuss important insights into the potential of CPAF as a component of an anti-chlamydial vaccine.