Since its initial characterization over 20 years ago, there has been intense and unwavering interest in understanding the role of the transcription factor cAMP-responsive element binding protein (CREB) in nervous system physiology. Through an array of experimental approaches and model systems, researchers have begun to unravel the complex and multifaceted role of this transcription factor in such diverse processes as neurodevelopment, synaptic plasticity, and neuroprotection. Here we discuss current insights into the molecular mechanisms by which CREB couples synaptic activity to long-term changes in neuronal plasticity, which is thought to underlie learning and memory. We also discuss work showing that CREB is a critical component of the neuroprotective transcriptional network, and data indicating that CREB dysregulation contributes to an array of neuropathological conditions.