Although sleep seems an obvious and simple behaviour, it is extremely complex involving numerous interactions both at the neuronal and the molecular levels. While we have gained detailed insight into the molecules and neuronal networks responsible for the circadian organization of sleep and wakefulness, the molecular underpinnings of the homeostatic aspect of sleep regulation are still unknown and the focus of a considerable research effort. In the last 20 years, the development of techniques allowing the simultaneous measurement of hundreds to thousands of molecular targets (i.e. ‘omics’ approaches) has enabled the unbiased study of the molecular pathways regulated by and regulating sleep. In this chapter, we will review how the different omics approaches, including transcriptomics, epigenomics, proteomics, and metabolomics, have advanced sleep research. We present relevant data in the framework of the two-process model in which circadian and homeostatic processes interact to regulate sleep. The integration of the different omics levels, known as ‘systems genetics’, will eventually lead to a better understanding of how information flows from the genome, to molecules, to networks, and finally to sleep both in health and disease.