It has now been established that sleep deprivation or fragmentation causes hyperalgesia which cannot be explained by a general change in somatosensory perception. However, it has not yet been clarified which of the sleep stages are most relevant for this effect. The seemingly paradoxical effects of sleep deprivation on pain-evoked brain potentials on the one hand and the subjective pain report on the other hand suggest complex changes in gating mechanisms. As the effects on pain and affect can be dissociated a common mechanism of action seems unlikely. Data from animal studies suggest that hyperalgesia due to sleep deprivation might be particularly strong under preexisting neuropathic conditions. Together with results from animal research the finding that endogenous pain modulation (CPM) is impaired by sleep deprivation suggests that the serotoninergic system mediates the effect of sleep deprivation on pain perception. However, other neurotransmitters and neuromodulators still have to be considered. The clinically relevant question arises why sleep deprivation induces hyperalgesia more easily in certain individuals than in others and why this effect then has a longer duration?