Using extracellular single unit recordings alone or in combination with neurobiotin juxtacellular labeling and orexin (hypocretin) immunohistochemistry in the mouse, we have recorded a total of 452 neurons in the orexin neuron field of the posterior hypothalamus. Of these, 76 exhibited tonic discharge highly specific to wakefulness, referred to as waking-active neurons. They showed differences from each other in terms of spike shape, activity profile, and response to an arousing sound stimulus and could be classified into three groups on the basis of spike shape as: 1) biphasic broad; 2) biphasic narrow; and 3) triphasic. Waking-active neurons characterized by biphasic broad spikes were orexin-immunopositive, whereas those characterized by either biphasic narrow or triphasic broad spikes were orexin-immunonegative. Unlike waking-specific histamine neurons, all orexin and non-orexin waking-active neurons exhibited slow (<10 Hz) tonic discharges during wakefulness and ceased firing shortly after the onset of electroencephalogram (EEG) synchronization (deactivation), the EEG sign of sleep (drowsy state). They remained virtually silent during slow-wave sleep, but displayed transient discharges during paradoxical (or rapid eye movement) sleep. During the transition from sleep to wakefulness, both orexin and triphasic non-orexin neurons fired in clusters prior to the onset of EEG activation, the EEG sign of wakefulness, and responded with a short latency to an arousing sound stimulus given during sleep. In contrast, the biphasic narrow non-orexin neurons fired in single spikes either prior to, or after, EEG activation during the same transition and responded to the stimulus with a longer latency. The activity of all waking-active neurons preceded the return of muscle tonus at the transition from paradoxical sleep to wakefulness. These data support the view that the activity of orexin and non-orexin waking-active neurons in the posterior hypothalamus plays an important wake-promoting role and that their activity antagonizes cortical deactivation and loss of muscle tone.