Neuronal activity is required for the survival of specific populations of neurons, for the proper synaptic organization of the visual and somatosensory cortex, and for learning and memory. The biochemical mechanisms that couple brief neuronal activity to rapid and lasting adaptive changes within the nervous system are poorly understood. Over a decade ago, it was first shown that mimicking neuronal activity by membrane depolarization rapidly induced the expression of a class of genes known as immediate early genes. Subsequently, it has been shown that neuronal activity triggers a temporal sequence of gene expression that has been suggested to play a role in mediating long-term adaptive responses. A major mechanism coupling neuronal electrical activity and the intracellular biochemical processes that culminate in gene expression is Ca2+ influx through plasma membrane Ca2+ channels. In this review, we delineate some of the reported mechanisms by which Ca2+ regulates gene expression: from its ability to activate specific intracellular signal transduction pathways to its ability to regulate the initiation, elongation, and translation of RNA transcripts. We will discuss some known mechanisms by which different patterns of Ca2+ influx, or Ca2+ influx through different types of channel, could generate distinct patterns of gene expression and how our understanding of Ca2+-regulated gene expression relates to larger questions of activity-dependent nervous system function.