Sleep parallels brain functioning and mental health. Neuronal activity during wakefulness leads to a subsequent increase in sleep intensity as measured using electroencephalographic slow-wave activity (SWA; index of neuronal synchrony in the low-frequency range). Wakefulness, and particularly prolonged wakefulness, also drives important changes in brain gene expression and changes in protein regulation. The role of these two cellular mechanisms in sleep-wake regulation has typically been studied independently, and their exact contribution to SWA remains poorly defined. In this review, we highlight that many transcriptional pathways driven by sleep deprivation are associated to protein regulation. We first describe the relationship between cytokines, clock genes, and markers of sleep need with an emphasis on transcriptional processes. Observations regarding the role of protein metabolism in sleep-wake regulation are then depicted while presenting interconnections between transcriptional and translational responses driven by sleep loss. Lastly, a manner by which this integrated response can feed back on neuronal network activity to determine sleep intensity is proposed. Overall, the literature supports that a complex cross-talk between transcriptional and translational regulation during prolonged wakefulness drives the changes in sleep intensity as a function of the sleep/wake history.