Vaginal drug delivery is a promising route for the treatment and prevention of local and systemic diseases such as genital herpes or AIDS. Suitable excipients must be selected to optimize the residence time of formulations in vaginal mucosa and could be included in the formulation. Many polymers are excellent choices for the development of vaginal drug delivery systems due to their properties of mucoadhesion, biocompatibility and biodegradability. These polymers swell in the aqueous medium of the vaginal environment and generate a gel layer which allows controlled release of the drug. The thickness and viscosity of the gel layer determine the drug release process. The aim of this chapter is to review the different polymers available for the development of vaginal delivery systems and to describe their physicochemical (swelling, viscosity, mucoadhesion), biopharmaceutical (drug release, biodegradability) and cytotoxic properties.