THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways(1,2). FKBP12- rapamycin inhibits progression through the G1 phase of the cell cycle in osteosarcoma(3), liver(4,5) and T cells(6,7) as well as in yeasts, and interferes with mitogenic signalling pathways that are involved in G1 progressiong(9,10), namely with activation of the protein p70(S6k) (refs 5, 11-13) and cyclin-dependent kinases(3,14-16). Here we isolate a mammalian FKBP-rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae(8,17,18). Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP-rapamycin complex directly(17,19), these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases(17-20).