Women account for a substantial majority of HIV infections in endemic regions, where women are also infected at a much younger age than men. Part of this epidemiological skewing is due to socio-cultural factors, but it is clear that biological factors enhance the susceptibility of women - particularly young women - to HIV acquisition after sexual exposure. These factors, including important differences in mucosal immunology at the site of genital HIV exposure, are the focus of this concise review. Compared to heterosexual men, women have an increased surface area of mucosal HIV exposure, increased mucosal expression of the HIV co-receptor CCR5 and a greater probability of virus exposure on the rectal mucosa. Differences that are specific to young women include a pro-inflammatory immune environment and a proportionate increase in single-cell, columnar genital epithelium. These important biological reasons for enhanced HIV susceptibility in young women highlight the need for targeted HIV prevention within this vulnerable population.