The immunosuppressants rapamycin and FK506 bind to the same intracellular protein, the immunophilin FKBP12. The FKBP12-FK506 complex interacts with and inhibits the Ca*+-activated protein phosphatase calcineurin. The target of the FKBPl2-rapamycin complex has not yet been identified. We report that a protein complex containing 245 kDa and 35 kDa components, designated rapamycin and FKBPlP targets 1 and 2 (RAFT1 and RAFTS), interacts with FKBPl2 in a rapamycin-dependent manner. Sequences (330 amino acids total) of tryptic peptides derived from the 245 kDa RAFT1 reveal striking homologies to the yeast TORgene products, which were originally identified by mutations that confer rapamycin resistance in yeast. A RAFT1 cDNA was obtained and found to encode a 269 kDa protein (2549 amino acids) that is 43% and 39% identical to TOR2 and TORl, respectively. We propose that RAFT1 is the direct target of FKBPlS-rapamycin and a mammalian homolog of the TOR proteins.