HIV is generally sexually acquired across the genital or rectal mucosa after exposure to the genital secretions of an HIV-infected partner. Most exposures to HIV do not result in infection, likely due to protection afforded by an intact mucosal epithelium, as well as by innate and adaptive mucosal immune factors present in the genital tract. Another important mucosal determinant of transmission may be the number and activation status of potential HIV target cells, including CCR5/CD4+ T cells and DC-SIGN+ dendritic cells. The simultaneous presence of other genital infections, including classical sexually transmitted infections (STIs), can enhance HIV susceptibility either by breaching the epithelial barrier, recruiting HIV target cells to the genital tract, or by generating a pro-inflammatory local immune milieu. In HIV-infected individuals, genital co-infections increase HIV levels in the genital secretions, thereby increasing secondary sexual transmission. Co-infections that act as important HIV cofactors include human cytomegalovirus (CMV), Herpes simplex virus type 2 (HSV2), Neisseria gonorrhoeae and many others. Strategies focused on genital co-infections, such as vaccines, microbicides and suppressive therapy, are feasible in the short term and have the potential to curb the pandemic.