Abstract Sleep and sleep loss are affecting protein synthesis in the brain, but the contribution of translational control to wakefulness and sleep regulation remains poorly understood. Here, we studied the role of two suppressors of protein synthesis, the eukaryotic translation initiation factor 4E-binding proteins 1 and 2 (4E-BP1 and 4E-BP2), in sleep architecture and electroencephalographic (EEG) activity as well as in the EEG and molecular responses to acute sleep loss. The EEG of mice mutant for the genes encoding 4E-BP1 or 4E-BP2 (Eif4ebp1 and Eif4ebp2 knockout [KO] mice) was recorded under undisturbed conditions and following a 6-hour sleep deprivation (SD). The effect of SD on the expression of genes known to respond to SD was also measured in the prefrontal cortex of Eif4ebp1 and Eif4ebp2 KO mice. Eif4ebp1 KO mice differed from wild-type mice in parameters of wakefulness and sleep quantity and quality, and more subtly in the gene expression response to SD. For instance, Eif4ebp1 KO mice spent more time in slow-wave sleep (SWS) and showed altered baseline 24-h time courses of SWS delta (1–4 Hz) activity and sigma (10–13 Hz) activity. Eif4ebp2 KO mice differed from wild-type mice only for wakefulness and sleep quality, expressing changes in EEG spectral activity generally revealed during and after SD. These findings suggest different roles of effectors of translational control in the regulation of wakefulness and sleep and of synchronized cortical activity.