The AMP-activated protein kinase (AMPK) is a central regulator of cellular and organismal metabolism in eukaryotes, activated when intracellular ATP levels decrease. It plays critical roles in regulating growth, metabolism, and autophagy. Recent studies have revealed new insights into AMPK's function, including its downstream effectors and mechanisms of activation. AMPK is a highly conserved sensor of intracellular nucleotide levels, activated by increases in AMP or ADP, leading to catabolic pathways that generate more ATP and inhibit anabolic pathways. Genetic studies in various organisms have shown that AMPK functions as a metabolic sensor, allowing adaptive changes in growth, differentiation, and metabolism under low-energy conditions. In mammals, AMPK coordinates growth and metabolism, with specialized roles in tissues like the liver, muscle, and fat. AMPK exists as a heterotrimer with catalytic and regulatory subunits. It is activated by a two-pronged mechanism involving nucleotide binding and phosphorylation of Thr172 in the activation loop. LKB1 and CAMKK2 are key upstream activators, with LKB1 also functioning as a tumor suppressor. AMPK is involved in various cellular processes, including cell growth, autophagy, and metabolism. It regulates the mTORC1 pathway by phosphorylating TSC2 and Raptor, inhibiting mTORC1 activity. AMPK also activates ULK1, which is critical for autophagy and mitochondrial homeostasis. AMPK coordinates cell growth and autophagy by inhibiting mTORC1 and activating ULK1. AMPK also regulates metabolism through transcriptional control and direct effects on metabolic enzymes. It phosphorylates and regulates transcription factors, coactivators, and enzymes involved in fatty acid and sterol synthesis. AMPK is involved in circadian clock regulation and metabolic reprogramming. It also plays a role in cell polarity, migration, and cytoskeletal dynamics by regulating proteins such as CLIP-170 and E-cadherin. AMPK's role in these processes is increasingly recognized, with studies showing its involvement in cell polarity and cytoskeletal dynamics. AMPK's signaling pathways converge with other pathways such as PI3K and Erk, highlighting its role as a master coordinator of cell growth, metabolism, and cell fate. The identification of AMPK's downstream effectors provides new targets for therapeutic interventions in diseases such as diabetes, cancer, and neurological disorders. Future research aims to define the relative contribution of AMPK and other stress-sensing pathways in metabolic dysfunction and insulin resistance. Overall, AMPK is a key regulator of cellular and organismal metabolism, with broad implications for health and disease.The AMP-activated protein kinase (AMPK) is a central regulator of cellular and organismal metabolism in eukaryotes, activated when intracellular ATP levels decrease. It plays critical roles in regulating growth, metabolism, and autophagy. Recent studies have revealed new insights into AMPK's function, including its downstream effectors and mechanisms of activation. AMPK is a highly conserved sensor of intracellular nucleotide levels, activated by increases in AMP or ADP, leading to catabolic pathways that generate more ATP and inhibit anabolic pathways. Genetic studies in various organisms have shown that AMPK functions as a metabolic sensor, allowing adaptive changes in growth, differentiation, and metabolism under low-energy conditions. In mammals, AMPK coordinates growth and metabolism, with specialized roles in tissues like the liver, muscle, and fat. AMPK exists as a heterotrimer with catalytic and regulatory subunits. It is activated by a two-pronged mechanism involving nucleotide binding and phosphorylation of Thr172 in the activation loop. LKB1 and CAMKK2 are key upstream activators, with LKB1 also functioning as a tumor suppressor. AMPK is involved in various cellular processes, including cell growth, autophagy, and metabolism. It regulates the mTORC1 pathway by phosphorylating TSC2 and Raptor, inhibiting mTORC1 activity. AMPK also activates ULK1, which is critical for autophagy and mitochondrial homeostasis. AMPK coordinates cell growth and autophagy by inhibiting mTORC1 and activating ULK1. AMPK also regulates metabolism through transcriptional control and direct effects on metabolic enzymes. It phosphorylates and regulates transcription factors, coactivators, and enzymes involved in fatty acid and sterol synthesis. AMPK is involved in circadian clock regulation and metabolic reprogramming. It also plays a role in cell polarity, migration, and cytoskeletal dynamics by regulating proteins such as CLIP-170 and E-cadherin. AMPK's role in these processes is increasingly recognized, with studies showing its involvement in cell polarity and cytoskeletal dynamics. AMPK's signaling pathways converge with other pathways such as PI3K and Erk, highlighting its role as a master coordinator of cell growth, metabolism, and cell fate. The identification of AMPK's downstream effectors provides new targets for therapeutic interventions in diseases such as diabetes, cancer, and neurological disorders. Future research aims to define the relative contribution of AMPK and other stress-sensing pathways in metabolic dysfunction and insulin resistance. Overall, AMPK is a key regulator of cellular and organismal metabolism, with broad implications for health and disease.