In silico docking of a chemical library with the ligand binding domain (LBD) of thyroid hormone nuclear receptor- (TR) suggested that farnesyl pyrophosphate (FPP), a key intermediate in cholesterol synthesis and protein farnesylation, might function as an agonist. Surprisingly, addition of FPP to cells activated TR as well as the classical steroid hormone receptors but not peroxisome proliferative activating receptors, farnesol X receptor, liver x receptor, or several orphan nuclear receptors whose ligands are unknown. FPP enhanced receptor-coactivator binding in vitro and in vivo and elevation of FPP levels in cells by squalene synthetase or farnesyl transferase inhibitors leads to activation. The FPP effect was blocked by selective receptor antagonists, and in silico docking with 143 nuclear receptor LBD structures revealed that FPP only docked with the agonist conformation of those receptors activated by FPP. Our results suggest that certain nuclear receptors maintain a common structural feature that may reflect an action of FPP on an ancient nuclear receptor or that FPP could function as a ligand for one of the many orphan nuclear receptors whose ligands have not yet been identified. This finding also has potential interesting implications which may, in part, explain the pleotropic effects of statins as well as certain actions of farnesylation inhibitors in cells.