The forebrain cholinergic neurons are localized in the nucleus basalis magnocellularis (NBM), the major source of cholinergic innervation to the neocortex and to the amygdala, and in the medium septum-banda diagonalis complex, which provides cholinergic inputs to the hippocampus (Mesulam et al. 1983; Woolf et al. 1984; Nicoll 1985). Basic and clinical studies have linked dysfunctions of these neurons to cognitive decline (Everitt and Robbins 1997; Givens and Sarter 1997). Their extensive loss is characteristic of the forebrain of Alzheimer's disease patients (Davies and Maloney 1976; Coyle et al. 1983; Kuhl et al. 1999), and anticholinergic drugs, such as scopolamine and atropine, produce learning and memory deficits in a variety of cognitive animal models (Deutsch 1971; Bartus and Johnson 1976; Ennaceur and Meliani 1992), and affect recognition memory in humans (Sperling et al. 2002; Sherman et al. 2003). Moreover, aged rodents display both cognitive impairments in many learning tasks (Ingram et al. 1994) and cholinergic deficits (Kubanis and Zornetzer 1981; Decker 1987; Gallagher and Colombo 1995). However, neuronal alterations associated with cognitive deficits are not restricted to the cholinergic systems. For instance, dysfunctions of dopamine, GABA, noradrenaline, serotonin, and histamine neurons have been identified in Alzheimer's disease (Hardy et al. 1985; Airaksinen et al. 1991; Panula et al. 1997; Schneider et al. 1997), and region-selective decreases in dopaminergic, noradrenergic, or serotonergic contents are associated with the level of age-related learning and memory impairments (Stemmelin et al. 2000; Birthelmer et al. 2003). Abnormal interactions between malfunctioning cholinergic and other neurotransmitter systems may cause additive or even synergistic effects on cognition, a phenomenon that warrants the increasing interest in understanding the complex physiology of brain systems affecting cognitive processes. In this regard, the role of histamineis gaining increasing attention (Passani et al. 2000; Passani and Blandina 2003), and many recent results indicate that the histaminergic system influences learning and memory by modulating the release of ACh (Passani et al. 2000; Bacciottini et al. 2001), although some cognitive effects of histamine and histaminergic agents occur independently of ACh. For example, local administration of histamine failed to affect ACh release from the hippocampus (Bacciottini et al. 2002), yet improved fear memory by H2- or H3-receptor-elicited erk2 activation in hippocampal CA3 cells (Giovannini et al. 2003). Nevertheless, histaminergic efferents influence both the NBM-cortical (Clapham and Kilpatrick 1992; Blandina et al. 1996; Cecchi et al. 2001) and the medium septum-banda diagonalis-hippocampal cholinergic pathways (Mochizuki et al. 1994; Bacciottini et al. 2002; Fig. 1). The regulation of ACh tone in different brain areas by neuronal histamine also encompasses functions other than cognition. Histamine promotes wakefulness by tonic control over sleep-generating mechanisms in the preoptic/anterior hypothalamus, and cholinergic neurons seem to be implicated (Lin et al. 1994; Brown et al. 2001). The aim of this review is to summarize some of the most recent work on the interactions between histaminergic and cholinergic systems, and evaluate their role in cognitive and other brain functions. (Contains 2 figures.)