Histaminergic neurons of the tuberomammillary nucleus (TMN) are hypothesized to promote wakefulness, but little is known about the activity of these cells during spontaneous behavior. We measured histaminergic neuron activity in the dorsomedial, ventrolateral, and caudal TMN at four different times using Fos and adenosine deaminase immunohistochemistry and recordings of sleep/wake behavior. Because circadian factors could influence neuronal activity, we then assessed TMN neuron activity in predominantly sleeping or awake animals, all killed at the same time of day. In both experiments, Fos expression in histaminergic neurons of all three TMN subnuclei was higher during periods of wakefulness. These results demonstrate that histaminergic neurons throughout the TMN are wake-active, and this activity is largely independent of the time of day.