 The leading cause of preventable blindness and most common bacterial sexually transmitted infection, chlamydia trachomatis, has seen remarkable progress in vaccine research over six decades. But questions remain about the role of specific cellular populations and molecular mechanisms in protective immunity against genital tract infections. Biomarkers for vaccine-induced protective immunity are elusive in humans, and animal models have limitations in translating data to human pathogens. This commentary discusses recent advances in chlamydia vaccine development and their implications for a rational approach to designing a human cetachomatis vaccine. This article was authored by Stephen Liang, David Buehler, Churu Korshik, and others.