The histaminergic system profoundly influences various brain functions, spanning from movement and cognition to regulating satiety, pain perception, the cycle of sleep and wakefulness, motor functions, and neuroimmune reactions. Histamine actions are primarily coupled to the stimulation of the histamine type 1 (H1R), type 2 (H2R), type 3 (H3R), and type 4 (H4R) receptors, which belong to the G protein-coupled receptor (GPCR) family. Histamine receptors play distinct roles in cellular responses: H1R and H2R primarily exert excitatory actions. In contrast, H3Rs act as inhibitory auto- and heteroreceptors, allowing them to influence both the histaminergic system and other neurotransmitter systems. H4Rs, meanwhile, are primarily involved in mediating inflammatory responses. This diversity highlights the intricate roles of histamine both in normal physiological processes and in disease states. Moreover, histamine and its receptors play a pivotal function in neuroinflammation, resulting in greater awareness of their importance in central nervous system disorders like Alzheimer’s disease, depression, disorders in sleep, schizophrenia, and Parkinson’s disease among others. This chapter is focused on brain histamine receptors, their intracellular pathways, and their involvement in some brain disorders.