In this review I have discussed the importance of barriers retarding the transport of electrolytes, non-electrolytes, proteins, and water to the maintenance of physiological homeostasis, and how disruption of these barriers can lead to severe pathological consequences. At the cellular level, I have discussed the potential localization of these barriers to molecular diffusion as being at the intercellular junction, plasmalemmal membrane, and at the extracellular surface of the plasma membrane. The presence of barriers in the major organ systems of the body is noted and these are listed, together with the physiological need for their restrictive-permeability properties. Emphasis is then placed on 2 of these barriers, the blood-brain barrier and the gastric mucosal barrier, and common characteristics of these systems are discussed. I have outlined our present knowledge of the molecular basis of the gastric mucosal barrier and, specifically, the contribution of the surface barrier constituents: mucus, bicarbonate, and surface-active lipids (glycolipids and phospholipids). Lastly, I have discussed our recent experiments pertaining to the possible importance of a hydrophobic water-repellent lining to the stomach's resistance to luminal acid.