The TSC1–TSC2 complex, composed of the tumor suppressor proteins hamartin (TSC1) and tuberin (TSC2), plays a crucial role in controlling cell growth by regulating mTORC1 (mammalian target of rapamycin complex 1). The complex acts as a molecular switchboard, integrating signals from various cellular pathways to modulate mTORC1 activity. TSC1 and TSC2 form a heterodimeric complex, with TSC2 containing a GAP (GTPase-activating protein) domain that negatively regulates mTORC1 through its interaction with the small G-protein Rheb. Rheb, which is activated by amino acids and growth factors, stimulates mTORC1 activity. The TSC1–TSC2 complex is phosphorylated on multiple sites by various kinases, including PI3K-Akt, ERK-ASK, and IKKβ, which alter its function and GAP activity towards Rheb. This complex also integrates signals from energy and oxygen sensing pathways, cell cycle regulators, and stress signaling pathways. Abnormal activation of mTORC1, often driven by mutations in TSC genes or other upstream regulators, is a common feature in various hamartoma syndromes and cancers, suggesting that dysregulation of the TSC1–TSC2 complex may contribute to tumorigenesis and cancer progression. However, the limited malignancy potential of TSC-related tumors may be due to multiple mechanisms that attenuate Akt signaling, a potent oncoprotein. Proper regulation of the TSC1–TSC2 complex by Akt is essential for maintaining metabolic homeostasis, and aberrant mTORC1 signaling has been linked to insulin resistance. Despite significant progress, many aspects of the complex's regulation and function remain to be fully understood.The TSC1–TSC2 complex, composed of the tumor suppressor proteins hamartin (TSC1) and tuberin (TSC2), plays a crucial role in controlling cell growth by regulating mTORC1 (mammalian target of rapamycin complex 1). The complex acts as a molecular switchboard, integrating signals from various cellular pathways to modulate mTORC1 activity. TSC1 and TSC2 form a heterodimeric complex, with TSC2 containing a GAP (GTPase-activating protein) domain that negatively regulates mTORC1 through its interaction with the small G-protein Rheb. Rheb, which is activated by amino acids and growth factors, stimulates mTORC1 activity. The TSC1–TSC2 complex is phosphorylated on multiple sites by various kinases, including PI3K-Akt, ERK-ASK, and IKKβ, which alter its function and GAP activity towards Rheb. This complex also integrates signals from energy and oxygen sensing pathways, cell cycle regulators, and stress signaling pathways. Abnormal activation of mTORC1, often driven by mutations in TSC genes or other upstream regulators, is a common feature in various hamartoma syndromes and cancers, suggesting that dysregulation of the TSC1–TSC2 complex may contribute to tumorigenesis and cancer progression. However, the limited malignancy potential of TSC-related tumors may be due to multiple mechanisms that attenuate Akt signaling, a potent oncoprotein. Proper regulation of the TSC1–TSC2 complex by Akt is essential for maintaining metabolic homeostasis, and aberrant mTORC1 signaling has been linked to insulin resistance. Despite significant progress, many aspects of the complex's regulation and function remain to be fully understood.