Kinetically inert Group 9 metal complexes have found emerging use as inhibitors of protein kinases or as modulators of protein-protein interactions. A series of cyclometalated rhodium(III) and iridium(III) complexes was investigated as inhibitors of mammalian target of rapamycin (mTOR) activity. Cell-free and cell-based experiments revealed rhodium(III) complex 1 to be a potent mTOR inhibitor (IC50=0.01 μM in the cell-free system), with potency comparable to that of rapamycin. The inhibition by complex 1 was found to be dependent on FK506-binding protein 12 (FKBP12), which suggests that complex 1 may behave as a modulator of the mTOR-FKBP12 interaction. Preliminary structure-activity relationships indicated that the donor ligand and the nature of the metal center are important determinants for mTOR inhibitory activity. Rhodium(III) complex 1 represents the first metal-based inhibitor of mTOR activity, and demonstrates the potential of kinetically inert Group 9 complexes as protein-protein interaction modulators. Limiting activity: The first metal-based inhibitor of mammalian target of rapamycin (mTOR) activity has been found. The cyclometalated rhodium(III) complex 1 (see scheme) inhibits mTOR activity in cell-free and cell-based systems. The size and hydrophobicity of the N N donor ligand and the nature of the metal center are determinants for mTOR inhibitory activity. The inhibitory effect of 1 is also dependent on FK506-binding protein 12.