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The structure of the human FK506 binding protein (FKBP), complexed with the immunosuppressant FK506, has been determined to 1.7 angstroms resolution by x-ray crystallography. The conformation of the protein changes little upon complexation, but the conformation of FK506 is markedly different in the bound and unbound forms. The drug's association with the protein involves five hydrogen bonds, a hydrophobic binding pocket lined with conserved aromatic residues, and an unusual carbonyl binding pocket. The nature of this complex has implications for the mechanism of rotamase catalysis and for the biological actions of FK506 and rapamycin.