Glutamine addiction is a critical therapeutic target in cancer, as cancer cells rely heavily on glutamine for growth and survival. Unlike glucose, which is primarily used for energy, glutamine serves as a nitrogen donor for nucleotide and amino acid biosynthesis, and is essential for maintaining mitochondrial function and redox balance. Cancer cells exhibit a high rate of glutamine uptake, which is not solely due to its role in nitrogen supply but also because it supports essential amino acid uptake and TOR kinase activation. Glutamine is the primary mitochondrial substrate, contributing to NADPH production and maintaining mitochondrial membrane potential. Glutamine is crucial for the synthesis of nonessential amino acids, such as serine, alanine, aspartate, and ornithine, through enzymatic steps involving nitrogen transfer. It also activates the mTORC1 signaling pathway, which is vital for protein synthesis and cell growth. The mTORC1 is responsive to both glutamine and essential amino acids (EAAs), and its activation is regulated by the Ras homolog enriched in brain (RHEB) GTPase, which is released from repression by tumor suppressors. Oncogenic levels of c-MYC regulate glutamine metabolism by activating genes involved in nucleotide biosynthesis and glutamine transport. Myc also promotes the metabolism of imported glutamine into glutamic acid and lactic acid, contributing to anaplerosis and NADPH production. Myc overexpression enhances glutamine catabolism, leading to glutamine addiction in cancer cells. Targeting glutamine metabolism in cancer includes inhibiting glutamine transporters, such as SLC1A5 (ASCT2), and blocking glutamine-dependent pathways like glutaminolysis. Inhibitors such as GPNA and BCH can suppress glutamine uptake and mTORC1 activation, inducing autophagy. Additionally, compounds like L-asparaginase and phenylbutyrate can deplete glutamine levels, disrupting cancer cell growth. Metformin, a biguanide, inhibits mitochondrial respiration and may target cancer cells by reducing glutamine metabolism. However, its efficacy in cancer therapy is still under investigation. Targeting glutamine metabolism offers a promising approach for cancer treatment, as cancer cells are highly dependent on glutamine for survival. Future research aims to develop therapies that exploit this dependency, potentially leading to new treatments for glutamine-addicted cancers.Glutamine addiction is a critical therapeutic target in cancer, as cancer cells rely heavily on glutamine for growth and survival. Unlike glucose, which is primarily used for energy, glutamine serves as a nitrogen donor for nucleotide and amino acid biosynthesis, and is essential for maintaining mitochondrial function and redox balance. Cancer cells exhibit a high rate of glutamine uptake, which is not solely due to its role in nitrogen supply but also because it supports essential amino acid uptake and TOR kinase activation. Glutamine is the primary mitochondrial substrate, contributing to NADPH production and maintaining mitochondrial membrane potential. Glutamine is crucial for the synthesis of nonessential amino acids, such as serine, alanine, aspartate, and ornithine, through enzymatic steps involving nitrogen transfer. It also activates the mTORC1 signaling pathway, which is vital for protein synthesis and cell growth. The mTORC1 is responsive to both glutamine and essential amino acids (EAAs), and its activation is regulated by the Ras homolog enriched in brain (RHEB) GTPase, which is released from repression by tumor suppressors. Oncogenic levels of c-MYC regulate glutamine metabolism by activating genes involved in nucleotide biosynthesis and glutamine transport. Myc also promotes the metabolism of imported glutamine into glutamic acid and lactic acid, contributing to anaplerosis and NADPH production. Myc overexpression enhances glutamine catabolism, leading to glutamine addiction in cancer cells. Targeting glutamine metabolism in cancer includes inhibiting glutamine transporters, such as SLC1A5 (ASCT2), and blocking glutamine-dependent pathways like glutaminolysis. Inhibitors such as GPNA and BCH can suppress glutamine uptake and mTORC1 activation, inducing autophagy. Additionally, compounds like L-asparaginase and phenylbutyrate can deplete glutamine levels, disrupting cancer cell growth. Metformin, a biguanide, inhibits mitochondrial respiration and may target cancer cells by reducing glutamine metabolism. However, its efficacy in cancer therapy is still under investigation. Targeting glutamine metabolism offers a promising approach for cancer treatment, as cancer cells are highly dependent on glutamine for survival. Future research aims to develop therapies that exploit this dependency, potentially leading to new treatments for glutamine-addicted cancers.