There is renewed interest in the development of long-term, controlled-release dosage forms for the intravaginal delivery of antiretrovirals for HIV prophylaxis. This interest has catalyzed a renaissance in vaginal drug delivery, increasing the fundamental understanding of determinants of controlled drug delivery in the vagina as well as development of new materials, delivery platforms, and animal models. Our goal in writing this review from the perspective of engineers and pharmaceutical scientists interested in prevention of sexually transmitted infections is to highlight the current state of the art, progress in preclinical programs, new drug-delivery device designs, and to discuss some of the important unknowns in this area of HIV prevention for the general audience involved in HIV research. As far as antiretrovirals are concerned, this review is limited to programs working with antiretrovirals that are supported with an investigational new drug filing. We draw primarily from published papers in the PubMed and CAS databases, however, many of the most recent advances have yet to appear in the peer-reviewed literature and for this class of publications we draw from a recent formulation workshop held by CONRAD as well as from the Microbicides, Controlled Release Society, and CROI meetings.