Sleep is a fundamental behavior characterized by a state of inactivity, which has been observed in a wide range of species. Despite its conservation in evolution, the precise purpose of sleep remains shrouded in mystery. The application of innovative tools has significantly contributed to the exploration of the regulating mechanisms and functions involved in sleep, although further investigations is still required. In this thesis, I have examined sleep in two different contexts, using Drosophila melanogaster as model system. In the first part of this work, I combined a range of transcriptomics and immunostaining experiments, to analyze how gene expression changes in the brain upon acute and chronic sleep deprivation (SD) and found a role for histone methylases in regulating sleep-specific changes in gene expression. Prolonged SD leads to an overall decrease in gene expression driven by inhibitory histone methylation activity (H3K9) in the brain. The specific removal of H3K9 methylases, such as Su(var)3-9 or G9a, in neurons, interferes with this process, blocking sleep-specific changes in gene expression and canceling the fly’s internal homeostatic control of sleep. In the second part of this thesis, I dissected the recently hypothesized function of sleep, in facilitating DNA repair mechanisms. DNA damages, in particular double-stranded breaks (DSBs), are known to accumulate in the brain during wakefulness and decrease during sleep. Pharmacologically induction of DSBs leads to an increased baseline sleep in flies. Moreover, the pan-neuronal reduction of DNA repair-related genes, particularly p53, promotes increased sleep: the combination of chronic SD with the knockdown of p53 leads to heightened levels of neuronal DSBs and a reduction in lifespan. Unravelling the cellular basis for sleep drive may facilitate the improvement in restorative sleep quality for individuals dealing with sleep disorders and provide valuable insights into the relationship between sleep, aging, and neurodegenerative diseases.