Although the transcription factor CREB has been widely implicated in memory, whether it is sufficient to produce spatial memory under conditions that do not normally support memory formation in mammals is unknown. We found that locally and acutely increasing CREB levels in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions that do not normally support spatial memory, weakly trained wild-type (WT) mice and strongly trained mutant mice with a brain-wide disruption of CREB function. Together with previous results, these findings indicate that CREB is both necessary and sufficient for spatial memory formation, and highlight its pivotal role in the hippocampal molecular machinery underlying the formation of spatial memory.