Moruzzi pioneered the notion of ascending activating systems that were responsible for the electrophysiological activation characterizing the transition from sleep to waking. This paper proposes to extend the notion of electrophysiological activation to the domain of gene expression. Evidence is reviewed indicating that in the transition between sleep and waking there is, together with a change in neuronal firing patterns, a change in patterns of gene expression in widespread regions of the brain. The hypothesis is presented that changes in the activity of neuromodulatory systems with diffuse projections may subserve the diffuse, tonic and phasic activation of both neuronal responses and of gene expression. Finally, the paper discusses the possibility that such changes in gene expression may be of importance for plastic phenomena and for the functional consequences of sleep.