Histamine is highly conserved in the evolution as a signaling molecule, a neuromodulator, and a neurotransmitter from bacteria to mammals that fulfills basic demands of living like the organization of behavioral state. From mussels to mammals, it gates ion channels as an ionotropic transmitter or modulator. These relatively neglected functions are treated for arthropods and mollusks. In vertebrate brains, histamine actions are mostly mediated by three of the four known G-protein-coupled histamine receptors: H1R, H2R, and H3R. Histamine also modifies other receptor proteins through allosteric interactions. We describe and discuss the anatomical, biophysical, and physiological properties of histaminergic neurons as well as their projections and actions on target neurons.