The cAMP-response element (CRE)-binding protein CREB is a transcription factor that regulates multiple cellular processes, including long-term memory, in organisms ranging from Aplysia to humans. However, the specific transcriptional programs related to long-term memory that are regulated by CREB are unknown. Coleen Murphy and colleagues conducted the first in vivo genome-wide screen for CREB transcriptional targets involved in regulation of long-term memory (Neuron 85, 330–345, 2015). The authors compared transcriptional profiles between CREB-null and wild-type Caenorhabditis elegans before and after training for olfactory long-term associative memory. They identified 757 transcripts that were induced in a CREB- and training-dependent manner. Only 37 of the corresponding genes contained CRE sequences. Thus, most of the CREB/training-regulated genes are likely indirect targets of CREB and would not have been identified through in vitro binding assays. This gene set was distinct from non-training-induced CREB targets and was enriched for neuronal transcripts and gene ontology terms including behavior, ion channel activity and intracellular signaling. Many of these genes are also known to function in neuronal processes, including memory, in mammals. Previously uncharacterized genes in the gene set may point to new memory components.