The transcription factor Myc is essential for metabolic reprogramming in activated T cells. Upon T cell activation, Myc is induced and drives the shift from fatty acid β-oxidation and pyruvate oxidation via the TCA cycle to glycolysis, pentose phosphate pathway, and glutaminolysis. This metabolic reprogramming is associated with a global change in the metabolic transcriptome, which is driven by Myc. While both HIF1α and Myc are induced upon T cell activation, only Myc is required for the metabolic reprogramming. Myc is necessary for T cell proliferation and growth, and its deletion impairs activation-induced glycolysis and glutaminolysis. Myc also regulates the expression of metabolic enzymes and transporters involved in glycolysis and glutaminolysis. Myc-dependent glutaminolysis is linked to the biosynthesis of polyamines and ornithine, which are essential for T cell proliferation. The study shows that Myc is a critical regulator of T cell metabolism and that its activity is essential for the metabolic reprogramming that supports T cell growth and proliferation. The findings suggest that Myc-dependent metabolic pathways are essential for T cell function and that targeting these pathways could be a potential therapeutic strategy for diseases involving T cell dysfunction.The transcription factor Myc is essential for metabolic reprogramming in activated T cells. Upon T cell activation, Myc is induced and drives the shift from fatty acid β-oxidation and pyruvate oxidation via the TCA cycle to glycolysis, pentose phosphate pathway, and glutaminolysis. This metabolic reprogramming is associated with a global change in the metabolic transcriptome, which is driven by Myc. While both HIF1α and Myc are induced upon T cell activation, only Myc is required for the metabolic reprogramming. Myc is necessary for T cell proliferation and growth, and its deletion impairs activation-induced glycolysis and glutaminolysis. Myc also regulates the expression of metabolic enzymes and transporters involved in glycolysis and glutaminolysis. Myc-dependent glutaminolysis is linked to the biosynthesis of polyamines and ornithine, which are essential for T cell proliferation. The study shows that Myc is a critical regulator of T cell metabolism and that its activity is essential for the metabolic reprogramming that supports T cell growth and proliferation. The findings suggest that Myc-dependent metabolic pathways are essential for T cell function and that targeting these pathways could be a potential therapeutic strategy for diseases involving T cell dysfunction.