The intestinal mucosa is composed of multiple barriers to the lumen-to-blood transport of solutes, including the unstirred water and mucous layers, the apical and basolateral cell membranes of the epithelial cell, the paracellular junctions, the interstitial matrix, and the capillary and lymphatic endothelia. The epithelial barrier appears effectively to restrict the movement of solutes with a radius as low as 3 A, yet it also permits limited permeation by molecules as large as albumin (36 A radius). There is evidence to suggest that the restrictive properties of the gastrointestinal mucosa are significantly altered under various physiological and pathological conditions, and measurement of plasma (or luminal) clearances of water-soluble molecules has proved to be a popular method for studying intestinal permeability. The aim of this review is to discuss the concept of the plasma clearance method, methodological aspects of the technique, factors that influence plasma-to-lumen clearance measurements (e.g. solute size, blood flow, and permeability of the epithelial cell barrier), and advantages and disadvantages of the clearance method. Finally, application of the clearance technique to the study of ischaemia/reperfusion-, ethanol-, and FMLP-induced mucosal injury will be described.