Although women bear a disproportionate burden of HIV infection, little is known about HIV acquisition in the female reproductive tract. To bridge this gap, a structured and systematic set of mucosal immunology studies have been embedded in the CAPRISA 002 Acute Infection Study, the CAPRISA 004 and CAPRISA 008 Microbicide trials to understand heterosexual HIV transmission at the predominant site of HIV entry in women. This chapter reviews the major events from the past decade leading to the establishment of the CAPRISA Mucosal Laboratory and includes a synopsis of the key contributions this program has provided to advancing understanding of HIV infection in women. These have important implications for the design of more targeted HIV prevention interventions for women. Notable advances in understanding genital inflammation, the causes thereof, and its link to HIV acquisition are highlighted. These data are important in enhancing our understanding of the divergent pre-exposure prophylaxis (PrEP) trial findings in women and informing the development of future women-initiated HIV prevention technologies.