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Abstract: The physiological and neuroendocrine functions of the pineal gland hormone, melatonin, and its therapeutic potential critically depend on the understanding of its target sites and its mechanisms of action. This has progressed considerably in the last few years through the cloning of G protein-coupled seven-transmembrane melatonin receptors (Mel1a and Mel1b) as well as of nuclear receptors (RZR/RORα and RZRβ) that are associated with melatonin signaling. The transcription factor RZR/RORα appears to mediate a direct gene regulatory action of the hormone, and specific binding sites have been identified in promoter regions of a variety of genes, such as 5-lipoxygenase (5-LO), p21WAF1/CIP1, and bone sialoprotein (BSP). The membrane signaling pathway clearly shows higher ligand sensitivity than the nuclear signaling pathway, but details of its signal transduction cascade, and target genes are presently unknown. Membrane melatonin receptors are expressed mainly in the central nervous system, whereas RZR/RORα is prominently expressed both in the periphery and the brain. The action of membrane melatonin receptors and their specific agonists have been associated with circadian rhythmicity, whereas direct effects of melatonin in the periphery, such as immunomodulation, cellular growth, and bone differentiation, mainly appear to be mediated by RZR/RORα. It is hypothesized in this review that, in some cases, RZR/RORα may be a primary target of membrane melatonin receptors.