Several lines of evidence indicate that the histaminergic (HA) system is important for wakefulness and behavioral state regulation. We investigated the hypothesis that age-related changes in HA system occur which may be related to decreased alertness in aging. Although histidine decarboxylase mRNA levels did not change with age in C57BL/6 mice, significant differences were found in histamine H1 receptor ( H 1R ), histamine H2 receptor ( H 2R ), and histamine H3 receptor ( H 3R ) mRNA levels in several brain regions. The most widespread changes were observed in H 1R mRNA, which were significantly lower (27–38%) in the cortex, hypothalamus, hippocampus and medulla of 24-month-old mice relative to 3-month-old animals. Age-related changes in H 2R mRNA levels were restricted to the pons and cerebellum and decreased H 3R mRNA was found only in the medulla. In conjunction with the age-related decrease in hypocretin receptor 2 mRNA levels we have previously reported, decreased HA receptor mRNA levels may contribute to diminished alertness, sleep continuity, and diurnal rhythms of sleep and wakefulness in the aged.