Oral delivery of agents such as vaccines offers a number of significant advantages over parenteral routes, yet only a small number of oral vaccines are routinely available today. The small intestine contains lymphoid aggregates that are overlaid by M cells. These aggregates are part of the gut-associated lymphoid tissues and are important for determining host responses to particulate antigenic material within the small intestine. Differentiating the receptor requirements for M cell uptake and transcytosis of bacterial antigen from the intestine has progressed although the specific signalling mechanisms that initiate antigen uptake and specifically target antigen to these cells is still relatively unknown. Microbial pathogen-associated molecular patterns (PAMPs) are recognised by the innate immune system through pattern recognition receptors (PRRs) either through direct receptor-bacterial ligand or endogenous adaptor-bacterial molecule interactions. PRRs on the surface of M cells that have been identified as important in antigen transcytosis include toll-like receptor-4, platelet-activating factor receptor and a5߱ integrin. A number of these PRRs are also found on neighbouring enterocytes and therefore the pathways signalled by receptor-ligand binding may differentially trigger different transduction pathways. Elucidation of these signalling pathways may assist in the design of effective oral vaccines that target the gut-associated lymphoid tissue.