Immunoreactive NPY neurons are widely distributed in the hypothalamus of several mammalian species. In the rat, dense NPY fiber networks are found in the paraventricular, suprachiasmatic and arcuate nuclei. NPY-containing cell bodies are mostly found in the arcuate nucleus. Studies performed at the electron microscope level clearly indicate that NPY is concentrated in dense core vesicles in the cytoplasm of cell bodies as well as in terminals. Only a small percentage (about 20%) of the NPY endings are making synaptic contacts with nerve processes, especially dendrites. These ultrastructural data suggest that NPY might play a neurotransmitter/neuromodulator role. NPY has been shown, when injected into hypothalamic areas, to exert a variety of effects, including modifications in food intake, energy balance and pituitary secretion. In an attempt to define the exact role of NPY in hypothalamic functions, we have designed experiments to study the interactions of NPY with other neurotransmitter systems. In the suprachiasmatic nucleus, both NPY and 5-HT terminals have been shown to establish synaptic junctions sometimes with the same neurons. Occasionally, axoaxonic junctions between these two types of endings have been observed. These results suggested that both 5-HT and NPY might be involved in the complex regulation of circadian rythms. In the arcuate nucleus, nonsynaptic appositions between 5-HT nerve endings and NPY-containing neurons were demonstrated. In this nucleus, direct appositions between TH- and NPY-containing neurons were also detected. These appositions were of axosomatic, axodendritic or axoaxonic types. Since it has been demonstrated that arcuate NPY neurons are projected to other hypothalamic areas, such as the paraventricular and dorsomedial nuclei, it might be speculated that arcuate 5-HT/NPY and catecholamines/NPY interactions might be involved in regulation of behavior and neuroendocrine functions.