The origin of afferent connections of the hypothalamic tuberomammillary nucleus has been examined by using retrograde and anterograde tracing techniques. Retrogradely labeled neurons were found in about 70 cell groups of the forebrain and brainstem after injection of tracer into the ventral subgroup of the tuberomammillary nucleus. The majority of the labeled neurons were seen in the forebrain, with particularly large numbers in the infralimbic cortex, lateral septal nucleus, and preoptic region. The anterograde tracing experiments supported the general results of the retrograde tracing experiments. However, we did not observe any single cell group that selectively projected to the cell-rich core of the nucleus. In general, only a few fibers entered the core, whereas many labeled fibers seemed to terminate immediately adjacent to the cell group. Thus the target for the afferents is not primarily the perikarya of the neurons of the tuberomammillary nucleus, but either dendrites radiating out from the nucleus or neurons not belonging to the tuberomammillary nucleus. The results of the present study demonstrate that the histaminergic tuberomammillary nucleus derives its main input from the limbic forebrain. Through their widespread projections, the histaminergic neurons may transmit information originating from the limbic system to most if not all parts of the brain.