Transcriptional activation is a key process required for long-term memory formation. Recently, the transcriptional coactivator CREB-binding protein (CBP) was shown to be critical for hippocampus-dependent long-term memory and hippocampal synaptic plasticity. As a coactivator with intrinsic histone acetyltransferase activity, CBP interacts with numerous transcription factors and contains multiple functional domains. Currently, it is not known which transcription factor-binding domain of CBP is essential for memory storage. Using mice that carry inactivating mutations in the CREB-binding (KIX) domain of the coactivator CBP ("CBP"[superscript KIX/KIX] mice), we show that the KIX domain is required for long-term memory storage. These results are the first to identify an in vivo function for the KIX domain of CBP in the brain, and they suggest that KIX-interacting transcription factors recruit CBP histone acetyltransferase activity during long-term memory storage. One such KIX-interacting factor is the transcription factor CREB. Using quantitative real-time RT-PCR, we find that the expression of specific CREB target genes is reduced in the hippocampi of "CBP"[superscript KIX/KIX] mice during memory consolidation. The recruitment of the transcriptional coactivator CBP via the KIX domain thus imparts target gene-dependent selectivity to CREB-driven transcriptional regulation, thereby activating genes required for the long-term storage of hippocampus-dependent memory.