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Highlights • Externally supplied Glutamine (Gln) in involved in the maintenance of intracellular levels of ATP in the parasite. • Gln is able to extend the parasite’s survival under severe metabolic stress. • Gln is involved in the differentiation from the non-infective stage (epimastigote) to the infective stage (metacyclic trypomastigote). • In most stages of T. cruzi , glutamine is alternately supplied by its intracellular biosynthesis or by its uptake in a compensatory manner. Abstract Trypanosoma cruzi , the aetiological agent of Chagas disease, can obtain L-glutamine (Gln) through the enzyme glutamine synthetase (GS) using glutamate (Glu) and ammonia as substrates. In this work, we show additional non-canonical roles for this amino acid: its involvement in ATP maintenance and parasite survival under severe metabolic stress conditions and its participation in the differentiation process occurring in the insect vector (metacyclogenesis). These roles are dependent on the supply of Gln from an extracellular source. We show that T. cruzi incorporates Gln through a saturable and specific transport system, which results in unusual stability at elevated temperatures. The activity was moderately higher at pH values between 6 and 7 and was sensitive to the dissipation of the H+ gradient at the plasma membrane. When analysed in the different life cycle stages, we found that Gln transport is developmentally regulated. In fact, Gln uptake and GS activity seem to be finely regulated at most stages: when GS activity is increased, transport is decreased and vice versa , with the exception of trypomastigotes, where both sources of Gln are diminished. This metabolic adaptation reflects the relevance of Gln in T. cruzi biology and the plasticity of these parasites to adjust their metabolism to changing environments. [ABSTRACT FROM AUTHOR]