Over 30 publications suggest that antigens given orally to mice in biocompatible microspheres stimulate an immune response and, in some cases, can give rise to protective immunity. Of those responses in mice that have been reproduced, confirmation in large animal models and in Phase 1 studies has not resulted. Particles containing antigens given orally and mixed with soluble adjuvants like cholera toxin have generally not produced any better data in mice than that seen with mixed solutions of unprotected antigens and adjuvants. Peyer's patch M cell targeting of antigens in particles remains however a relatively untested hypothesis. While binding and uptake of M cell-targeted latex particles and stable liposomes by mouse M cells has been clearly shown using the mouse M cell-specific lectin, Ulex europaeus 1 (UEA-1), a direct relationship between M cell particle uptake and immune outcome remains illusive. Some studies have produced increased serum antibodies from UEA-1- and cholera toxin B (CTB)-coated liposomes containing antigens. Other groups are currently working on developing novel human M cell ligands for attachment to stable particles for oral delivery. Use of untargeted antigen-containing particles with adjuvants administered by the nasal route remains an alternative option.