Mitochondria are signaling organelles that regulate a wide variety of cellular functions and can dictate cell fate. Recent evidence has shown that TCA cycle intermediates, traditionally viewed as biosynthetic products, also function as signaling molecules that control chromatin modifications, DNA methylation, the hypoxic response, and immunity. This review summarizes the mechanisms by which TCA cycle metabolites control cellular function and fate in different contexts. The TCA cycle is a central metabolic pathway that generates reducing equivalents (NADH and FADH2) for the electron transport chain (ETC), which is essential for oxidative phosphorylation (OXPHOS). The TCA cycle is tightly regulated and its activity is closely linked to OXPHOS. TCA cycle intermediates such as acetyl-CoA, α-KG, succinate, fumarate, and L-2-HG have non-metabolic signaling roles in physiology and disease. Acetyl-CoA regulates chromatin dynamics and histone acetylation, which affects gene expression and cellular functions. α-KG is a key modulator of the hypoxic response and epigenetic modifications. It is a substrate for 2-OGDD enzymes that regulate histone and DNA demethylation. 2-HG, a metabolite derived from α-KG, can inhibit these enzymes and has roles in immune and stem cell functions. Succinate and fumarate are oncometabolites that promote tumorigenesis by inhibiting PHDs and causing pseudohypoxia. Itaconate, derived from the TCA cycle, has anti-inflammatory properties and can inhibit isocitrate lyase. The review highlights the signaling implications of TCA cycle metabolites and how changes in their abundance control physiology and disease. The TCA cycle and its metabolites play a crucial role in cellular signaling, influencing gene expression, chromatin modifications, and immune responses. Future research may uncover additional mechanisms by which TCA cycle metabolites exert signaling functions beyond post-translational modifications. The use of TCA cycle metabolite derivatives in therapeutic applications is an emerging area of interest.Mitochondria are signaling organelles that regulate a wide variety of cellular functions and can dictate cell fate. Recent evidence has shown that TCA cycle intermediates, traditionally viewed as biosynthetic products, also function as signaling molecules that control chromatin modifications, DNA methylation, the hypoxic response, and immunity. This review summarizes the mechanisms by which TCA cycle metabolites control cellular function and fate in different contexts. The TCA cycle is a central metabolic pathway that generates reducing equivalents (NADH and FADH2) for the electron transport chain (ETC), which is essential for oxidative phosphorylation (OXPHOS). The TCA cycle is tightly regulated and its activity is closely linked to OXPHOS. TCA cycle intermediates such as acetyl-CoA, α-KG, succinate, fumarate, and L-2-HG have non-metabolic signaling roles in physiology and disease. Acetyl-CoA regulates chromatin dynamics and histone acetylation, which affects gene expression and cellular functions. α-KG is a key modulator of the hypoxic response and epigenetic modifications. It is a substrate for 2-OGDD enzymes that regulate histone and DNA demethylation. 2-HG, a metabolite derived from α-KG, can inhibit these enzymes and has roles in immune and stem cell functions. Succinate and fumarate are oncometabolites that promote tumorigenesis by inhibiting PHDs and causing pseudohypoxia. Itaconate, derived from the TCA cycle, has anti-inflammatory properties and can inhibit isocitrate lyase. The review highlights the signaling implications of TCA cycle metabolites and how changes in their abundance control physiology and disease. The TCA cycle and its metabolites play a crucial role in cellular signaling, influencing gene expression, chromatin modifications, and immune responses. Future research may uncover additional mechanisms by which TCA cycle metabolites exert signaling functions beyond post-translational modifications. The use of TCA cycle metabolite derivatives in therapeutic applications is an emerging area of interest.