Within this review we will provide a comprehensive understanding in order to improve existing strategies and to develop new systems to lower the barrier for improving mucosal drug delivery. Mucosal administration of drugs achieves a therapeutical effect as the permeation of significant amounts of a drug is permitted through the absorption membrane. The absorption membrane relies on the mucosal layer and the epithelial tissue. In order to overcome barriers, drug delivery systems have to exhibit various functions and features, such as mucoadhesive and protective activity, solubility improving, permeation and uptake enhancing, and drug release controlling properties. This review also aims to provide an insight of well-distinguished strategies to date, as well as provide a focus on the enhancement of membrane permeability. Furthermore, since the development and functions of drug delivery systems exert a high influence on the ability of drug permeation through membrane, these considerations will also be discussed in this review.