Mucosal immune responses are in the first line of defense against most infections and protective mucosal immunity can be achieved by mucosal vaccination. However, mucosal tolerance and physicochemical features of the mucosal environment pose challenging obstacles to the development of mucosal vaccines. Vaccine formulations must be designed to enhance stability at the mucosae and incorporate features that induce innate immunity at mucosal inductive sites. To face these challenges, a number of novel delivery systems for targeting of mucosal vaccines to specific mucosal locations have been developed. In addition, specific mucosal immune cell targeting can potentially be achieved with ligand-antigen bioconjugates, in particular, those directed to specific receptors expressed on Microfold (M) cells, mucosal epithelial cells, or mucosal antigen presenting cells (APCs). In this topical review, targeted strategies to enhance the effectiveness of mucosal vaccines are addressed, and obstacles to the design and progression of effective ligand-mediated mucosal vaccines are highlighted.