Mammalian target of rapamycin (mTOR) is an atypical protein kinase that belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family and is involved in controlling cell growth in response to environmental cues. It is a shared component of two distinct complexes, mTORC1 and mTORC2, that integrate signals from various cellular pathways and exhibit differential sensitivity to rapamycin. Though it was previously established that a complex between rapamycin and the protein FKBP12 inhibits mTOR by interacting with its FRB domain, the molecular mechanism involved has remained unclear. Now, Pavletich and colleagues provide unprecedented mechanistic insights into the activity and regulation of this key metabolic enzyme by solving the crystal structure of a 1,500-amino-acid fragment of mTOR comprising the FAT, FRB, kinase and FATC domains bound to mLST8, a component of mTORC1 and mTORC2. The mTOR–mLST8 complex exhibits a compact shape—with mLST8 and the FRB domain protruding from the kinase domain—and displays a well-ordered activation loop stabilized by FATC-domain interactions. Cocrystals of the same complex with Mg2+ and ADP or with the ATP transition-state mimic MgF3 reveal a catalytic-cleft conformation consistent with intrinsic activity in the absence of other mTORC components. Comparison with CDK2, also bound to MgF3, indicates that mTOR uses a canonical protein-kinase catalytic mechanism rather than a lipid-kinase mechanism proposed for the primordial PI3K Vps34. The new structure also indicates that access to mTOR's catalytic cleft is partially occluded by the FRB domain, whereas a model constructed by overlaying the structure of the isolated FRB domain bound to rapamycin–FKBP12 suggests that a near-complete occlusion of the catalytic cleft is the basis for rapamycin-mediated inhibition. Several previously identified hyper-activating mutations map to elements seen to limit active site access, and this suggests that active site restriction is a key component of mTOR regulation. However, binding of the mTOR substrate S6K to the FRB domain is also shown to facilitate the phosphorylation of S6K by mTOR, a result indicating a function of the FRB domain in recruiting substrates to the active site. Given the central role of mTOR in regulating cell growth, and that its deregulation is often observed in disease states such as cancer and type 2 diabetes, mTOR represents a promising therapeutic target. By reporting the structures of mTOR–mLST8 bound to selective (Torin2 and PP242) or dual-specificity (PI-103) inhibitors, Pavletich and colleagues also provide a useful structural framework for understanding the potency and specificity of ATP-competitive compounds toward mTOR. (Nature 497, 217–223, 2013)