The electrophysiological properties of the sleeping brain profoundly influence memory function in various species, yet the molecular nature of sleep-memory interaction remains unclear. This article summarizes work that has established the cAMP-PKA-CREB intracellular signaling pathway as a major mechanism in the wakeful consolidation of memory while highlighting newer evidence that this pathway has a role in sleep regulation, in sleep deprivation, and potentially in sleep-memory interactions. It also explores the possibility that sleep might influence memory processing during a sort of molecular replay. The role of new approaches in understanding the nature of sleep-memory interactions is also discussed.