This chapter reviews the experimental evidence for an association between the circadian and the homeostatic phases of sleep regulation at the molecular level. Variability in the dynamics of the sleep homeostat could be expected to contribute to modifications in the habitual sleep duration and in the sensitivity to increased sleep pressure. As in the mouse, the factors contributing to differences of the dynamics of sleep homeostasis are likely to be genetic. The first line of evidence that supports a role of clock genes in sleep homeostasis involves the observation that elevated sleep pressure changes the expression of clock genes in various brain areas. Clock genes respond to increased neuronal activity and influence synaptic plasticity and the expression of synaptic elements determining synaptic strength. The increasing knowledge on the homeostatic regulation of the various aspects of sleep has led to hypotheses concerning sleep's still elusive functions.