The hypothalamus is responsible for the homeostasis of the whole body: the vegetative nervous system, energy administration and behavioral state. Its posterior part contains the two waking centers with complementary but distinct functions: the histaminergic system in the tuberomamillary nucleus and the orexin / hypocretin neurons in the neighboring perifornical area which both send their multifold arborizing axons all over the brain. These nuclei are silenced during sleep (non-REM and REM) by the sleep-active GABAergic neurons in the ventrolateral preoptic area (VLPO). The histamine neurons are pacemakers displaying intrinsic properties similar to other aminergic neurons, such as wide action potentials, Ca2+-prepotentials, a non-inactivating Na+-current, cationic (HCN) currents and A-type K+-currents. Their activity and the production of histamine are under feedback control of the H3 autoreceptor. The waking action is ascribed mainly to the H1R- mediated excitation of target neurons in the cortex, thalamus and the cholinergic, noradrenergic, serotonergic systems. The H1R is coupled to PLC and activates cationic channels (TRPC) or inactivates K+-channels. The H2R activates adenylyl cyclase blocking long-lasting afterhyperpolarisations and the accommodation firing. This could mediate the quiet readiness of cortical neurons during attention. The histaminergic system is the major waking system. The orexin containing neurons fire during waking especially when muscle tone is high; they excite other wake active neurons: histaminergic, cholinergic, noradrenergic, serotonergic and some dopaminergic neurons which fire bursts when a primary reward is expected. Degeneration of orexin neurons is the cause of most cases of human narcolepsy. The orexin system is responsible for sleep architecture and involved in energy administration, motor and motivational aspects of waking, ensuring that sleep, waking and feeding take place at the right time and the right place.