The orphan receptors RZR alpha, RZR beta, ROR alpha 1, RZR alpha 2, ROR alpha 3, and ROR gamma form a subfamily within the superfamily of nuclear hormone receptors. Recently, experimental evidence that the pineal gland hormone melatonin is the natural ligand for these nuclear receptors has come to light. This discovery is rather surprising, given that most people in the field believed melatonin acts exclusively through membrane receptors. However, these new findings establish a nuclear signalling pathway for melatonin, i.e., direct ligand-induced control of target gene transcription, which most probably mediates part of the physiological functions of the hormone. Interestingly, the very recently identified first RZR/melatonin responding gene, 5-lipoxygenase, is not expressed in the brain and is not involved in circadian rhythmicity, but rather acts in the periphery, mainly in myeloid cells, as one of the key enzymes of allergic and inflammatory reactions. Thus, nuclear melatonin signalling opens up a new perspective in understanding the actions of the pineal gland hormone.