The review by Nissim Hay and Nahum Sonenberg provides an overview of the mammalian target of rapamycin (mTOR) pathway, focusing on its upstream regulators and downstream targets. mTOR is a conserved protein kinase that regulates cell growth and proliferation through the control of protein synthesis. The upstream components of the mTOR signaling pathway include nutrient sensors, growth factors, and energy metabolism. Nutrient availability, particularly amino acids, and growth factors such as insulin and IGF-1, activate mTOR through the PI3K/Akt pathway. The TSC1/TSC2 complex acts as a negative regulator of mTOR, with TSC2 being directly phosphorylated by Akt. Rheb, a small GTPase, is an upstream positive regulator of mTOR, acting downstream of PI3K/Akt and TSC1/TSC2. Energy metabolism, regulated by AMPK, also affects mTOR activity. The downstream targets of mTOR include components of the translation machinery, such as eIF4E, eIF4G, and eIF4B, as well as S6 kinase (S6K1/S6K2) and its targets, ribosomal protein S6 and elongation factor 2 (eEF2). The review discusses the mechanisms by which these targets are regulated by mTOR phosphorylation and dephosphorylation, highlighting the complex interplay between nutrient and growth factor signaling pathways in controlling mTOR activity.The review by Nissim Hay and Nahum Sonenberg provides an overview of the mammalian target of rapamycin (mTOR) pathway, focusing on its upstream regulators and downstream targets. mTOR is a conserved protein kinase that regulates cell growth and proliferation through the control of protein synthesis. The upstream components of the mTOR signaling pathway include nutrient sensors, growth factors, and energy metabolism. Nutrient availability, particularly amino acids, and growth factors such as insulin and IGF-1, activate mTOR through the PI3K/Akt pathway. The TSC1/TSC2 complex acts as a negative regulator of mTOR, with TSC2 being directly phosphorylated by Akt. Rheb, a small GTPase, is an upstream positive regulator of mTOR, acting downstream of PI3K/Akt and TSC1/TSC2. Energy metabolism, regulated by AMPK, also affects mTOR activity. The downstream targets of mTOR include components of the translation machinery, such as eIF4E, eIF4G, and eIF4B, as well as S6 kinase (S6K1/S6K2) and its targets, ribosomal protein S6 and elongation factor 2 (eEF2). The review discusses the mechanisms by which these targets are regulated by mTOR phosphorylation and dephosphorylation, highlighting the complex interplay between nutrient and growth factor signaling pathways in controlling mTOR activity.