The FK506 binding protein 51 (FKBP51) is best known as an Hsp90-associated co-chaperone that regulates the responsiveness of steroid hormone receptors. In human genetic association studies, FKBP51 has repeatedly been associated with emotion processing and numerous stress-related affective disorders. It has also been implicated in contributing to the glucocorticoid hyposensitivity observed in New World primates. More recently, several research groups have consistently shown a protective effect of FKBP51 knockout or knockdown on stress endocrinology and stress-coping behavior in animal models of depression and anxiety. The principal druggability of FKBP51 is exemplified by the prototypic FKBP ligands FK506 and rapamycin. Moreover, FKBP51 is highly suited for X-ray co-crystallography, which should facilitate the rational drug design of improved FKBP51 ligands. In summary, FKBP51 has emerged as a promising new drug target for stress-related disorders that should be amenable to drug discovery.