Recent studies on the effects of sleep deprivation on synaptic plasticity have yielded discrepant results. Sleep deprivation studies using novelty exposure as a means to keep animals awake suggests that sleep (compared with wake) leads to widespread reductions in net synaptic strength. By contrast, sleep deprivation studies using approaches avoiding novelty-induced arousal (i.e., gentle handling) suggest that sleep can promote synaptic growth and strengthening. How can these discrepant findings be reconciled? Here, we discuss how varying methodologies for the experimental disruption of sleep (with differential introduction of novel experiences) could fundamentally alter the experimental outcome with regard to synaptic plasticity. Thus, data from experiments aimed at assessing the relative impact of sleep versus wake on the brain may instead reflect the quality of the waking experience itself. The highlighted work suggests that brain plasticity resulting from novel experiences versus wake per se has unique and distinct features.