In conclusion, several trends are observed in regard to the phylogenetic development of the pineal organ, which are relevant for our understanding of the evolution of biological clock mechanisms. 1. The pineal organ of all vertebrates investigated thus far is capable of producing and releasing melatonin. Melatonin is rhythmically produced and released during darkness and, thus, represents an important neuroendocrine information on the ambient photoperiod. 2. The rhythmic production of melatonin is under control of endogenous oscillators and photoreceptor cells. In several nonmammalian species, these endogenous oscillators and photoreceptors are located within the pineal organ itself. In some avian species, the inherent rhythmicity of the pineal organ appears to be influenced by pacemakers located in other parts of the central nervous system. Their information may be transmitted to the pineal organ via the sympathetic innervation. This innervation develops progressively in the course of phylogeny. In mammals certain pinealocytes express proteins which are specific of retinal and pineal photoreceptors, but these proteins are obviously not involved in photoreception and phototransduction. The mammalian pineal organ lacks not only functioning photoreceptors, but also endogenous oscillators. The photoreceptor cells involved in regulation of the melatonin biosynthesis are located in the retina; the major endogenous oscillator is the suprachiasmatic nucleus (SCN) of the hypothalamus. Information from the retina and the SCN is transmitted to the mammalian pineal organ via a complex neuronal chain, whose last member is the sympathetic innervation originating from the superior cervical ganglion. This innervation is mandatory to maintain the rhythm of the melatonin biosynthesis in the mammalian pineal organ. Interestingly, the effects of noradrenaline, the major neurotransmitter in the sympathetic nerve fibers, displays opposite effects on the melatonin biosynthesis in birds and mammals: it stimulates the melatonin biosynthesis in the mammalian pineal organ, but inhibits the melatonin formation in the chicken. This conversion occurs at the level of the adrenoreceptors. 3. The intrapineal nerve cells giving rise to pinealofugal neuronal projections are reduced in the course of phylogeny. Nevertheless, direct neuronlike connections appear to exist between the pineal organ and the central nervous system of mammals. These projections originate from a population of pinealocytes. Whether such projections are involved in biological clock mechanisms remains an issue not yet resolved. The ontogenetic data reviewed support the notion that, in lower vertebrates, melatonin biosynthesis is primarily controlled by intrapineal photoreceptors, whereas, in mammals, it depends on retinal photoreceptors and the sympathetic innervation of the pineal.(ABSTRACT TRUNCATED AT 400 WORDS)