Nano-sized systems have shown promise for efficient vaginal drug delivery providing sustained drug release and enhanced permeation. In parallel with advancements in drug discovery of new vaginal therapeutic agents, such as peptides, proteins, nucleic material, antigens, hormones, and microbicides, nanoplatforms are gaining momentum as prospective vectors for these agents. Thus far, extensive research in this arena has been focused on local delivery to the mucus vagina. However, an improved understanding of vaginal route, advantages offered by the vaginal route including being non-invasive and bypassing hepatic first-effect metabolism, and recent success achieved by vaginal drug nanocarriers may open the door for extensive nanotechnology- based research to explore the viability of systemic administration via this route. The review analyzes the possibilities given by nanoplatform-based delivery systems in the vaginal delivery of active agents. Special insight is given to the most important aspects to be considered during nanomedicine development and preclinical evaluation, i.e., the anatomy and physiology of the vagina, advantages of vaginal route of drug administration, and barriers to vaginal drug delivery. Finally, an updated analysis of the recent advancements of nanomedicine technologies and their potential progress into the clinic is compiled in this work.