During the course of aging both activation and degenerative changes are found in the human hypothalamus. Degeneration may start around middle‐age in some neurotransmitter‐ or neuromodulator‐containing neurons. For instance, a decreased number of vasoactive intestinal polypeptide (VIP) neurons was observed in the suprachiasmatic nucleus (SCN) of middle‐aged males. The normal circadian fluctuations seen in the number of vasopressin (AVP) neurons in the SCN of young subjects diminished in subjects older than 50 years. Moreover, a sharp decline in cell number was found in the sexually dimorphic nucleus (SDN) after 50 years in males. On the other hand, many hypothalamic systems remain perfectly intact during aging like the oxytocin (OXT) neurons in the paraventricular nucleus (PVN). The AVP neurons in the PVN are activated during aging as appears from their increasing cell number. Also the corticotrophin‐releasing hormone (CRH) neurons of the PVN are activated in the course of aging, as indicated by their increased number and their increased AVP coexpression. Part of the infundibular nucleus, the subventricular nucleus, contains hypertrophic neurokinin B neurons in postmenopausal women. It can be concluded that a multitude of changes in the various hypothalamic nuclei may be the biological basis for many functional changes in aging, i.e., both endocrine and central alterations, and that only a minority of the possible human hypothalamic changes have so far been studied. Microsc. Res. Tech. 44:36–48, 1999. © 1999 Wiley‐Liss, Inc.