Despite the fact that rectal and vaginal drug administration routes are less frequently employed than the oral and parenteral ones, they offer a number of advantages that make them worth considering. Both areas have rich vasculature and allow for a relatively easy application. While the vaginal route is most commonly used for the administration of locally acting agents, the rectal route can be employed to obtain both local and systemic effects. However, in both administration sites, some difficulties related mostly to the physiological activity of the rectum and vagina can be encountered. One of the most important challenges regarding these routes is poor retention time at the administration site. This problem can be addressed by mucoadhesive formulations, in situ forming gels, or both applied simultaneously. In situ forming gels are liquid formulations that, upon contact with physiological conditions, transform into a gel. The factors inducing the transition comprise temperature, pH, and the presence of specific ions. The spectrum of available pharmaceutical excipients allowing for obtaining different in situ gelling effects is wide and diverse; however, in rectal and vaginal drug delivery, thermosensitive formulations are the most popularly employed. In this chapter, the most important aspects regarding rectal and vaginal drug absorption are discussed, as well as the polymers capable of forming gels in the rectal and vaginal environment, and the scientific research presenting findings referring to in situ forming gels.