The neurotransmitter histamine receives less attention compared with other biogenic amines, because of its moderate action in the central nervous system (CNS). However, recent evidence suggests that histamine plays an important role in multiple CNS disorders including insomnia, narcolepsy, Parkinson's diseases, schizophrenia, Alzheimer's disease, and cerebral ischemia. New insights are emerging into the potential roles of histamine receptors as targets for the treatment of these diseases. Although some histamine related agents have failed in clinical trials, current preclinical studies suggest that this neurotransmitter may still have extensive applications in treating CNS disorders, however, advanced studies are warranted. This review summarizes findings from animal models and clinical research on the role of histamine and its receptor ligands in the brain for treatment of CNS disorders. The development of novel histamine receptor ligands and gaining an in-depth understanding of their potential mechanisms are necessary stepping stones to unlock their wide-ranging applications in the clinical arena.