Gene transcription is a crucial step in the sequence of molecular, synaptic, cellular, and systems mechanisms underlying learning and memory. Here, we review the experimental evidence demonstrating that alterations in the levels and functionality of the methylated DNA-binding transcriptional regulator MeCP2 are implicated in the learning and memory deficits present in mouse models of Rett syndrome and "MECP2" duplication syndrome. The significant impact that MeCP2 has on gene transcription through a variety of mechanisms, combined with well defined models of learning and memory, make MeCP2 an excellent candidate to exemplify the role of gene transcription in learning and memory. Together, these studies have strengthened the concept that precise control of activity-dependent gene transcription is a fundamental mechanism that ensures long-term adaptive behaviors necessary for the survival of individuals interacting with their congeners in an ever-changing environment.