The consolidation of long-term memory requires protein and mRNA synthesis. A similar requirement has been demonstrated for learning-related synaptic plasticity in the gill-withdrawal reflex of Aplysia. The monosynaptic component of this reflex can be reconstituted in vitro, where it undergoes both short- and long-term increases in synaptic strength in response to serotonin (5-HT), a neurotransmitter released during behavioral sensitization, a simple form of learning. As with sensitization, the long-term synaptic modification is characterized by a brief consolidation period during which gene expression is required. We find that during this phase, the transcription factor Aplysia CCAAT enhancer-binding protein (ApC/EBP) is induced rapidly by 5-HT and by cAMP, even in the presence of protein synthesis inhibitors. Blocking the function of ApC/EBP blocks long-term facilitation selectively without affecting the short-term process. These data indicate that cAMP-inducible immediate-early genes have an essential role in the consolidation of stable long-term synaptic plasticity in Aplysia.