CALCINEURIN (CaN) is a calcium- and calmodulin-dependent protein serine/threonine phosphatase which is critical for several important cellular processes, including T-cell activation(1). CaN is the target of the immunosuppressive drugs cyclosporin A and FK506, which inhibit CaN after forming complexes with cytoplasmic binding proteins (cyclophilin and FKBP12, respectively)(2). We report here the crystal structures of full-length human CaN at 2.1 Angstrom resolution and of the complex of human CaN with FKBP12-FK506 at 3.5 Angstrom resolution. In the native CaN structure, an autoinhibitory element binds at the Zn/Fe-containing active site. The metal-site geometry and active-site water structure suggest a catalytic mechanism involving nucleophilic attack on the substrate phosphate by a metal-activated water molecule. In the FKBP12-FK506-CaN complex, the auto-inhibitory element is displaced from the active site. The site of binding of FKBP12-FK506 appears to be shared by other non-competitive inhibitors of calcine-urin, including a natural anchoring protein.