Glutamine metabolism is a critical aspect of cancer biology, with cancer cells heavily relying on glutamine for energy production, biosynthesis, and survival. This review discusses the role of glutamine metabolism in tumorigenesis and its potential as a therapeutic target. Glutamine is transported into cells via various transporters and can be metabolized to produce energy and biosynthetic intermediates. The enzymes involved in glutamine metabolism, such as glutaminase (GLS and GLS2), play key roles in cancer cell survival and proliferation. GLS is more broadly expressed in normal tissue and is thought to be critical in many cancers, while GLS2 is primarily expressed in the liver, brain, and pancreas. The regulation of these enzymes is influenced by various factors, including nutrient availability, post-translational modifications, and oncogenic drivers. Glutamine metabolism is also involved in the production of amino acids, nucleotides, and other metabolites essential for cancer cell growth. The metabolism of glutamine can support the synthesis of purines and pyrimidines, which are critical for DNA replication and cell division. Additionally, glutamine metabolism contributes to the production of reducing equivalents, which are important for maintaining cellular redox balance and supporting energy production. The role of glutamine in cancer is further highlighted by its involvement in the synthesis of glutathione, a key antioxidant that helps protect cancer cells from oxidative stress. The metabolism of glutamine also plays a role in autophagy, a cellular process that helps maintain cellular homeostasis and survival under stress conditions. Glutamine metabolism can influence autophagy through various mechanisms, including the regulation of mTOR activity and the production of ammonia. The complex relationship between glutamine metabolism and autophagy is an area of ongoing research. In the clinic, glutamine metabolism has been explored as a potential therapeutic target. Allosteric inhibitors of glutaminase, such as CB-839, have shown promise in preclinical studies and are currently being evaluated in clinical trials. The use of glutamine metabolism as a therapeutic target is further supported by the observation that many cancers are highly dependent on glutamine for survival and growth. However, the development of effective therapies targeting glutamine metabolism requires a deeper understanding of the underlying mechanisms and the heterogeneity of cancer cells. Overall, the study of glutamine metabolism in cancer has provided valuable insights into the metabolic reprogramming of cancer cells and has highlighted the potential of targeting glutamine metabolism as a therapeutic strategy. Further research is needed to fully understand the complex interplay between glutamine metabolism, oncogenic drivers, and the tumor microenvironment.Glutamine metabolism is a critical aspect of cancer biology, with cancer cells heavily relying on glutamine for energy production, biosynthesis, and survival. This review discusses the role of glutamine metabolism in tumorigenesis and its potential as a therapeutic target. Glutamine is transported into cells via various transporters and can be metabolized to produce energy and biosynthetic intermediates. The enzymes involved in glutamine metabolism, such as glutaminase (GLS and GLS2), play key roles in cancer cell survival and proliferation. GLS is more broadly expressed in normal tissue and is thought to be critical in many cancers, while GLS2 is primarily expressed in the liver, brain, and pancreas. The regulation of these enzymes is influenced by various factors, including nutrient availability, post-translational modifications, and oncogenic drivers. Glutamine metabolism is also involved in the production of amino acids, nucleotides, and other metabolites essential for cancer cell growth. The metabolism of glutamine can support the synthesis of purines and pyrimidines, which are critical for DNA replication and cell division. Additionally, glutamine metabolism contributes to the production of reducing equivalents, which are important for maintaining cellular redox balance and supporting energy production. The role of glutamine in cancer is further highlighted by its involvement in the synthesis of glutathione, a key antioxidant that helps protect cancer cells from oxidative stress. The metabolism of glutamine also plays a role in autophagy, a cellular process that helps maintain cellular homeostasis and survival under stress conditions. Glutamine metabolism can influence autophagy through various mechanisms, including the regulation of mTOR activity and the production of ammonia. The complex relationship between glutamine metabolism and autophagy is an area of ongoing research. In the clinic, glutamine metabolism has been explored as a potential therapeutic target. Allosteric inhibitors of glutaminase, such as CB-839, have shown promise in preclinical studies and are currently being evaluated in clinical trials. The use of glutamine metabolism as a therapeutic target is further supported by the observation that many cancers are highly dependent on glutamine for survival and growth. However, the development of effective therapies targeting glutamine metabolism requires a deeper understanding of the underlying mechanisms and the heterogeneity of cancer cells. Overall, the study of glutamine metabolism in cancer has provided valuable insights into the metabolic reprogramming of cancer cells and has highlighted the potential of targeting glutamine metabolism as a therapeutic strategy. Further research is needed to fully understand the complex interplay between glutamine metabolism, oncogenic drivers, and the tumor microenvironment.