Transmucosal surfaces bypass many limitations associated with conventional drug delivery (oral and parenteral routes), such as poor absorption rate, enzymatic activity, acidic environment and first-pass metabolism occurring inside the liver. However, these surfaces have several disadvantages such as poor retention time, narrow absorption window and continuous washout of the drug by the surrounding fluids. Electrospun nanofibers with their unique surface properties and encapsulation efficiency may act as novel drug carriers to overcome the challenges associated with conventional drug delivery routes, so as to achieve desired therapeutic responses. This review article provides detailed information regarding the challenges faced in the mucosal delivery of drugs, and the use of nanofiber systems as an alternative to deliver drugs to the systemic circulation, as well as local drug administration. The physiological and anatomical features of different types of mucosal surfaces and current challenges are systematically discussed. We also address future considerations in the area of transmucosal delivery of some important drugs.