The following overview reconsiders the three-process model of sleepiness regulation (homeostatic, circadian, and sleep inertia) from a thermophysiologic point of view. Our results gathered over the last decade indicate that the homeostatic aspect of sleepiness regulation (ie, buildup of sleepiness during wakefulness and its decay during sleep) is not related to the thermoregulatory system, whereas the two other processes of sleepiness regulation (ie, circadian and sleep inertia process) are clearly related to thermoregulation in humans. Distal skin temperature of hands and feet seems to be the crucial variable for the association between thermophysiology, sleepiness, and sleep. Increased distal skin temperature before a nocturnal sleep episode is a good predictor for short sleep-onset latency. The disappearance of sleep inertia after sleep or a nap episode shows very similar kinetics as distal vasoconstriction. Furthermore, relaxation-induced sleepiness (eg, after lying down, at lights-off, with thermal biofeedback training) also evokes an increase in distal skin temperatures. The reverse effect occurs at lights-on or a posture change from supine to standing, Therefore, in terms of thermophysiology, sleep inertia can be explained as the reverse of a relaxation process (ie, decrease in distal skin temperatures). Our results reinterpret the so-called “sleep-evoked” reduction of core body temperature as a consequence of relaxation-induced vasodilatation after lights-off. Sleep per se has no further thermoregulatory effect. Taken together, a thermophysiologic approach may provide a successful strategy to treat sleep-onset insomnia and alleviate sleep inertia.