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These data show that glutamine-utilizing cells possess molecular mechanisms to detect the availability of glutamine and to respond specifically to changes in the extracellular glutamine concentration.The amino acid glutamine plays a central role in nitrogen transport within the body and is a fuel for rapidly dividing cells, such as in the gut and the immune system. Plasma glutamine levels decline during critical illness, and therefore these cells suffer from glutamine starvation under these conditions. The present review summarizes data on the specific effect of extracellular glutamine on metabolism, function, stress response, and apoptosis of glutamine-utilizing cells.Glutamine starvation leads to an energy depletion that is associated with a reduced responsiveness to exogenous stimuli. In addition, glutamine-starving cells show a reduced expression of the 70 000 Mr heat shock protein, which is an important factor for cell survival, and contain a reduced level of the antioxidant glutathione. Recent findings show that the extracellular glutamine level affects the susceptibility of cells to different apoptosis triggers: whereas glutamine-starving cells are more sensitive to Fas ligand-mediated apoptosis, they are desensitized against the cytotoxic effects of TNF-α. In addition, this review summarizes current knowledge on the molecular mechanisms of glutamine sensing. It discusses the role of AMP-activated protein kinase, the cellular redox state, osmosignalling, the regulation of translation, and amino acyl transfer RNA synthetases.