The physiological impact of Na(+)-nutrient cotransport-dependent regulation of intestinal tight junction permeability has been controversial. Nonetheless, increased permeability of small intestinal mucosae and enterocyte tight junctions as a consequence of Na(+)-nutrient cotransport has been documented by a significant number of in vivo and in vitro studies. Some details of the intracellular signaling events that regulate this process have been described recently. The aims of this article are to: (i) review studies of tight junction regulation and paracellular nutrient absorption in mammalian intestine, (ii) identify potential applications of tight junction regulation, and (iii) summarize recent progress in defining molecular mechanisms that lead to altered tight junction permeability.