The drugs can be absorbed both locally and systemically through the vaginal and rectal route, which is a possible location for drug administration. More control over the distribution of drug molecules for local and systemic actions has been made possibly by the development of novel rectal drug delivery, including hollow-type suppositories, thermo-responsive and mucoadhesive liquid suppositories, and nanoparticulate systems. The use of mucoadhesive or bioadhesive polymers, pH or temperature-sensitive polymers, liposomes, nanoparticles, vaginal inserts, multiple emulsions, and hydrogels have all been developed to overcome the limitations of conventional dosage forms administered through the vaginal route. These approaches enabled controlled and prolonged drug release. The potential of rectal and vaginal drug delivery systems may be unlocked through ongoing study and development in this area of drug delivery. This chapter provides a comprehensive review of novel approaches to rectal and vaginal drug delivery.