Sleep occupies a peculiar place in our lives and in science, being both eminently familiar and profoundly enigmatic. Historically, philosophers, scientists and artists questioned the meaning and purpose of sleep. If Shakespeare’s verses from MacBeth depicting “Sleep that soothes away all our worries” and “relieves the weary laborer and heals hurt minds” perfectly epitomize the alleviating benefits of sleep, it is only during the last two decades that the growing understanding of the sophisticated sleep regulatory mechanisms allows us to glimpse putative biological functions of sleep. Sleep control brings into play various brain-wide processes occurring at the molecular, cellular, circuit, and system levels, some of them overlapping with a number of disease-signaling pathways. Pathogenic processes, including mood disorders (e.g., major depression) and neurodegenerative illnesses such Huntington’s or Alzheimer’s diseases, can therefore affect sleep-modulating networks which disrupt the sleep-wake architecture, whereas sleep disturbances may also trigger various brain disorders. In this review, we describe the mechanisms underlying sleep regulation and the main hypotheses drawn about its functions. Comprehending sleep physiological orchestration and functions could ultimately help deliver better treatments for people living with neurodegenerative diseases.