Vitreous substitutes are traditionally used to stabilize the retina after vitrectomy. In recent years, various approaches have been developed for using the vitreous substitute not only as a tamponade but also as a drug release system to tackle ocular diseases. This review provides an overview of the requirements for vitreous substitutes and discusses the current clinically applied as well as novel polymer-based vitreous substitutes as drug delivery systems, including their release mechanisms, efficiencies, challenges, and future perspectives.