Sleep became a subject of scientific research in the second half of the 19th century. Since sleep, unlike other physiological functions, cannot be attributed to a specific organ, there was no distinct method available to study sleep until then. With the development of physiology and psychology, and a rapidly increasing knowledge of the structure and functioning of the nervous system, certain aspects of sleep became accessible to objective study. A first step was to measure responsiveness to external stimuli systematically, during sleep, allowing a first representation of the course of sleep (Schlaftiefe=sleep depth). A second method was to register continuously the motor activity across the sleep-wake cycle, which allowed the documentation in detail of rest-activity patterns of monophasic and polyphasic sleep-wake rhythms, or between day or night active animals. The central measurement for sleep research, however, became the electroencephalogram in the 1930s, which allowed observation of the sleeping brain with high temporal resolution. Beside the development of instruments to measure sleep, prolonged sleep deprivation was applied to study physiological and psychological effects of sleep loss. Another input came from clinical and neuropathological observations of patients with pronounced disorders of the sleep-wake cycle, which for the first time allowed localisation of brain areas that are essentially involved in the regulation of sleep and wakefulness. Experimental brain stimulation and lesion studies were carried out with the same aim at this time. Many of these activities came to a halt on the eve of World War II. It was only in the early 1950s, when periods with rapid eye movements during sleep were recognised, that sleep became a research topic of itself. Jouvet and his team explored the brain mechanisms and transmitters of paradoxical sleep, and experimental sleep research became established in all European countries. Sleep medicine evolving simultaneously in different countries, with early centres in Italy and France. In the late 1960s sleep research and chronobiology began to merge. In recent decades, sleep research, dream research, and sleep medicine have benefited greatly from new methods in genetic research and brain imaging techniques. Genes were identified that are involved in the regulation of sleep, circadian rhythms, or sleep disorders. Functional imaging enabled a high spatial resolution of the activity of the sleeping brain, complementing the high temporal resolution of the electroencephalogram.