Sexually transmitted infections like HIV, HPV, and HSV-2, as well as unplanned pregnancy, take a huge toll on women worldwide. Woman-initiated multipurpose prevention technologies that contain antiviral/antibacterial drugs (microbicides) and a contraceptive to simultaneously target sexually transmitted infections and unplanned pregnancy are being developed to reduce these burdens. This review will consider products that are applied topically to the vagina. Rectally administered topical microbicides in development for receptive anal intercourse are outside the scope of this review. Microbicide and microbicide/contraceptive candidates must be rigorously evaluated in preclinical models of safety and efficacy to ensure that only candidates with favorable risk benefit ratios are advanced into human clinical trials. This review describes the comprehensive set of in vitro, ex vivo, and in vivo models used to evaluate the preclinical safety and antiviral efficacy of microbicide and microbicide/contraceptive candidates.