The treatment of memory disorders, such as the gradual weakening of memory with age, the ravages of Alzheimer’s disease and the cognitive deficits in various forms of mental retardation, may greatly benefit from a better understanding of the molecular and cellular mechanisms of memory formation. There is increasing interest in the possibility of pharmacologically enhancing learning and memory even in the absence of specific anatomically evident pathology. Substantial evidence in experimental systems ranging from molluscs to humans indicates that the cAMP response element binding protein (CREB) is a core component of the molecular switch that converts short- to long-term memory. Recent studies have greatly strengthened and refined our understanding of the role of CREB in learning and memory in mammals, in addition to providing greater insight into the molecular mechanisms of CREB regulation and function. This involvement of CREB and the upstream signalling pathways leading to its activation in learning-associated plasticity makes them attractive targets for drugs aimed at improving memory function, in both diseased and healthy individuals. However, CREB and its close relatives cAMP response element modulator and activating transcription factor-1 are ubiquitous proteins with several critical functions. This creates hurdles that the authors believe may limit the usefulness of CREB per se as a target for the development of memory-enhancing drugs, and focus on components of the upstream signalling pathways or on specific downstream targets will be required.