Abstract: At last, the crystal structure is revealed for the catalytically active mTOR kinase enzyme, a master regulator of cell growth. The structure indicates a gatekeeper mechanism that controls substrate access to the active site. See Article p.217 The mTOR (mammalian target of rapamycin) pathway is a central regulator of cell growth in response to environmental signals such as energy, nutrients and growth factors, and is misregulated in cancer and metabolic diseases. Here the first crystal structures of the mTOR kinase are presented. The 3.2 Å crystal structures of the enzyme bound to a positive regulator and to small-molecule ATP-competitive inhibitors reveal an intrinsically active kinase, and explain how the rapamycin–FKBP12 complex blocks recruitment of substrates to the kinase domain.