Human immunodeficiency virus, genital herpes, and other sexually transmitted infections are a critical national and global health priority requiring the rapid development of safe and effective control methods. Topical microbicides, self-administered agents designed for vaginal use, that block transmission at the mucosal surface may provide a realistic method of intervention that could be distributed worldwide. An optimal microbicide should protect against infection but must also be safe, without adversely affecting the mucosal environment, including mediators of host defense. Thus, a critical component in microbicides development is to identify optimal assays that could serve as surrogate markers to predict safety of microbicides prior to embarking on large-scale clinical trials. This will require a greater understanding of the mediators of mucosal immunity in the female genital tract.