The neuropathology of human sleep remains an ill-defined issue. The data concerning the main structures of human brain areas involved, or supposed to be implicated, in sleep organisation are reviewed. Five levels of organisation can be schematically recognized: (i) the ascending arousal system, (ii) the non REM and REM systems (iii) regulated by hypothalamic areas, (iv) and the biological clock, (v) modulated by a number of "allostatic" influences. These are briefly described, with emphasis on the location of structures involved in humans, and on the recently revised concepts. Current knowledge on the topography of lesions associated with the main sleep disorders in degenerative diseases is recalled, including REM sleep behavior disorders, restless legs syndrome and periodic leg movements, sleep apneas, insomnia, excessive daily sleepiness, secondary narcolepsy and disturbed sleep-wake rhythms. The lesions of sleep related structures observed in early and late stages of four degenerative diseases are then reviewed. Two synucleinopathies (Lewy lesions associated disorders, including Parkinson's disease and Dementia with Lewy bodies, and Multiple System Atrophy) and two tauopathies (Progressive Supranuclear Palsy and Alzheimer's disease) are dealt with. The distribution of lesions usually found in affected patients fit with that expected from the prevalence of different sleep disorders in these diseases. This confirms the current opinion that these disorders depend on the distribution of lesions rather than on their biochemical nature. Further studies might throw insight on the mechanism of normal and pathological sleep in humans, counterpart of the increasing knowledge provided by animal models. Specially designed prospective clinicopathological studies including peculiar attention to sleep are urgently needed.