Environment-driven metabolic reprogramming is a persistent feature throughout the life cycle of T cells and is essential for their normal development and functioning. Consequently, abnormal metabolic adaptation underpins a number of human diseases, including cancer. Although the great metabolic adaptation potential helps T cells to survive nutrient-restricted regions in the periphery and fulfill their duty in immune surveillance and other functions, it also helps T cell derived tumor cells to survive the nutrient-deprived tumor microenvironment, thus making them more resilient and difficult to combat. It has long been shown that cancer cells exhibit a metabolic shift from oxidative phosphorylation to aerobic glycolysis, a phenomenon known as the Warburg effect. A similar metabolic shift is also observed in activated T cells, suggesting a common mechanism between immune activation and tumorigenesis. However, this mechanism remains to be elucidated. The lymphoid-specific NF-κB family transcription factor c-Rel is a key regulator of B- and T-cell activation and immune response, and has been implicated in a number of hematopoietic cancers. To investigate the function and regulation of c-Rel in human T cells, we generated c-Rel knockout human T cell line Jurkat cells using the CRISPR/Cas9 system and analyzed the resulting phenotype. Our results revealed that c-Rel is a key metabolic regulator that facilitates T cell growth and proliferation by regulating energy metabolism to promote glycolysis and mitochondrial respiration. Disruption of c-Rel in Jurkat cells leads to dramatic reduction in cell growth and broad defects in both glycolysis and mitochondrial respiration. These metabolic defects are also observed in primary T cells isolated from c-Rel knockout mice, demonstrating c-Rel’s critical role in regulating T cell metabolism across species. Moreover, c-Rel knockout (KO) cells failed to adapt to nutrient-limited conditions and lost their proliferative capacity. Mechanistically, c-Rel is upregulated in response to nutrient stress and drives the expression of c-Myc – a potentiator of many genes in the glycolytic and mitochondrial respiratory pathway. Overexpression of c-Myc in c-Rel KO cells compensated for the loss of c-Myc induction under nutrient stress, and reversed the proliferative and metabolic defects. These results establish that c-Rel is a key stress responder and metabolic regulator that maintains cell growth and survival under nutrient stress and promotes the Warburg effect. Thus, strategies targeting c-Rel may provide an effective way to suppress cancer metabolism.