There has been a long history of experimentation and conjecture about a potentially critical role in memory consolidation for brain processes unique to sleep (1–3). A role for sleep in memory consolidation is consistent with the fact that new memory traces are not instantly fixed but rather remain susceptible to neuromodulatory influences for several hours after acquisition and require protein synthesis to become stable long-term memories (4). And while it has been clearly demonstrated that sleep deprivation can impair later memory for recently acquired declarative and procedural memory, the precise mechanisms by which sleep may aid or mediate memory storage processes are not known (3, 5). Activation of the cholinergic system has been demonstrated to enhance attention, learning, and memory consolidation and to facilitate plasticity after physiological manipulations and during development (6–8). Acetylcholine levels are high during waking and rapid eye movement (REM; also known as paradoxical) sleep (9). These observations seem consistent with the possibility that REM sleep may play an important role in facilitating synaptic plasticity of recently acquired memory traces. However, the great similarities between the waking and REM sleep states beg the question: What about REM sleep relative to waking is privileged for memory consolidation? Explicitly, REM sleep episodes follow deep slow-wave sleep (SWS) episodes. New findings by Gais and Born (10) presented in this issue of PNAS provide compelling evidence in human subjects that SWS and the accompanying low levels of acetylcholine during SWS may mediate a critical memory consolidation process. These findings support two-stage models …