The histaminergic nervous system, originating from histamine-producing neurons in the tuberomammillary nucleus (TMN) of the hypothalamus, plays a central role in a wide array of physiological and behavioral functions. These include regulating arousal, circadian rhythms, energy homeostasis, cognition, and motor behavior. Initially perceived as a homogeneous network, a growing body of evidence is uncovering the heterogeneity of histaminergic neurons, revealing functionally distinct subpopulations with specialized roles. This chapter reviews the evolving understanding of such diversity, highlighting advances in neuroanatomical, electrophysiological, genetic, and pharmacological approaches that have provided deeper insights into histamine’s complex role in the central nervous system (CNS). Techniques such as microdialysis, optogenetics, and 3D brain reconstructions have allowed a precise characterization of histaminergic neurons projections and related activity, revealing subpopulation-specific responses to different kinds of stimuli. This functional diversity underpins the histaminergic system’s influence on processes ranging from sleep-wake regulation to emotional behavior, memory, and social interactions. Notably, differential activation patterns across histaminergic subgroups, such as those responding specifically to different stressors, demonstrate the system’s adaptability and specialization. Additionally, interactions with other neurotransmitters, such as GABA, suggest potential co-transmission mechanisms that contribute to the nuanced modulation of neural circuits. Importantly, histaminergic dysfunctions have been implicated in several neurological and psychiatric disorders, including narcolepsy, Alzheimer’s disease, schizophrenia, and depression. The growing recognition of histaminergic neurons’ heterogeneity provides a critical framework for developing targeted therapeutic strategies. Advances in receptor modulation, such as H3 receptor antagonists, hold promise for improving cognitive function and mitigating sleep disturbances. However, despite recent breakthroughs in the field, there is still a need for continued research into the molecular and functional underpinnings of histaminergic diversity. The final goal of tailoring pharmacological interventions to specific neuronal subtypes, new approaches should be able to minimize side effects and enhance therapeutic efficacy. The intricate nature of the histaminergic system underscores its potential as a therapeutic target for a wide range of CNS disorders, paving the way for more personalized and effective treatments in the future.