Sexual transmission remains one of the most significant hurdles in the fight against HIV infection. The use of vaginal or rectal microbicides has been proposed for topical pre-exposure prophylaxis but available results from clinical trials of candidate products have been, at best, less than optimal. While waiting for the first product to get regulatory approval, novel approaches are being explored in order to enhance efficacy, as well as to assure safety. Strategies involving specific delivery of antiviral agents to key players involved in the early steps of sexual transmission have the potential to help achieving such purposes. Engineering systems that allow targeting cells, tissues or other biological structures of interest may provide a way to modulate local pharmacokinetics of promising microbicide molecules and, thus, maximize protection. This concise review discusses the identification and use of potential targets for such purpose, while detailing on several examples of targeted systems engineered as potential microbicide candidates. Furthermore, remaining challenges and hints for future work in the field of targeted microbicides are addressed.