Only a small number of oral vaccines are available for routine immunisations despite a significant research effort and a number of obvious advantages over parenteral vaccination. The major roadblock in the development of oral vaccines has been mostly attributed to a lack of ability to specifically target antigen to the mucosal immune system of the gastrointestinal tract. This commentary examines the accessing of M cells through receptor interaction on the apical surface of the cell in order to enhance the efficiency and efficacy of oral immunisation. Three challenges have been identified (i) the availability of appropriate experimental models to study M cell targeting and transcytosis; (ii) appropriate tools for investigating the specificity of targeting; and (iii) the identification of priority targets on the apical surface of M cells.