Sleep remains one of the great mysteries of evolution and biology. Despite the dangers that could accompany long periods of unresponsiveness to the external environment, every studied animal exhibits a sleep state. Much scientific deliberation has been dedicated to the search for a singular sleep function that could explain the persistence of sleep across species. However, decades of sleep research has shown that sleep is driven by a complex array of molecular signals that suggest that it likely serves multiple functions for the living organism. For my dissertation, I investigated the molecular mechanisms that underlie sleep regulation in the Drosophila melanogaster animal model. Also known as the common fruit fly, Drosophila sleep exhibits a high degree of conservation with mammalian sleep and provides many technical advantages for the sleep researcher. Chapter 1 of this dissertation provides an overview of the neurobiology of sleep in Drosophila based on data from most of the published literature on Drosophila sleep. This dissertation is divided into two major lines of inquiry. The first is described in Chapter 2 where I examine the role of Homer protein and metabotropic glutamate receptor interactions in sleep regulation. The second project examines the role of the PERK pathway — a regulator of global protein translation in the cell — in promoting sleep which is described in Chapter 3. In these projects, I used genetic and pharmacological approaches to interrogate the necessity of various molecules in Drosophila sleep. The results from these projects demonstrate a critical role for synaptic Homer proteins and PERK signaling in the endoplasmic reticulum in sleep regulation. Together, the findings from my dissertation provide greater insight into the molecular and neurobiological underpinnings of sleep behavior.