A topic of debate has been on the identity of the ancestral nuclear receptor as either a ligand-binding or an orphan receptor. This debate began more than twenty-five years ago when the first ligands were identified as mammalian steroid and thyroid hormones. Shortly thereafter, the identification of the ecdysone receptor in Drosophila introduced the idea that nuclear receptors were hormonal receptors that bind ligands with a nanomolar affinity. At the time, the three known nuclear receptor ligands were steroids, retinoids, and thyroid hormone, and of those three, both steroids and retinoids were products of terpenoid metabolism. Thus, it was postulated that ancestral receptor would have been liganded by a terpenoid molecule.