The intestine is exposed to a wide variety of macromolecules. Because macromolecules are antigenic, mechanisms have evolved in the gastrointestinal tract to regulate their absorption. Macromolecular uptake can be beneficial in delivering essential factors for growth and in sampling the antigenic milieu of the gastrointestinal tract. Specific transport mechanisms exist to execute this physiological absorption. However, inappropriate and uncontrolled antigen transport may occur in disease states or as a prelude to disease states in the gastrointestinal tract. Such transport may result in immune responses that are harmful. This review examines physiological transport of macromolecules through epithelia and through M cells. It also considers uncontrolled transport and its relation to disease states. The review concludes with an examination of the interrelationship between antigen transport and an altered immune system in the establishment of gastrointestinal disease.