An individual animal’s history of interaction with its environment—its “experience”—helps shape its neural circuitry and thus determines subsequent behavior. Experience during specific times in early life, referred to as critical periods, helps shape behaviors as diverse as maternal bonding and the acquisition of language. Correlated patterns of activity are thought to mediate critical periods by stabilizing concurrently active synaptic connections and weakening or eliminating connections whose activity is divergent. Some of this correlated activity depends on excitable properties of neurons that emerge prior to the influence of sensory-evoked, experience-dependent electrical signals, while other correlated activity is established by patterns of excitable changes elicited by sensory inputs or motor behaviors. The cellular and molecular mechanisms implicated in critical periods rely on the activity of several neurotransmitters, receptors, and intracellular signaling cascades that modify cytoskeletal integrity, receptor function and stability, and ultimately gene expression in response to changes in synaptic activity in a target cell. Receptors for the excitatory neurotransmitter glutamate, including the NMDA-R, AMPA-R, and metabotropic glutamate receptor (mGluR), are essential for the transduction of excitatory activity into postsynaptic changes that underlie critical period changes in circuits and behaviors. This transduction is often mediated by Ca2+ dependent second messenger systems in the post-synaptic cell activated by ligand or voltage gated channels. The intracellular signaling consequences rely upon the concerted activity of scaffolding proteins, protein kinases, and their targets that regulate the integrity of individual synapses as well as gene transcription, translation and protein stability. Genes for neurotrophins such as BDNF, extracellular matrix components, and neurotransmitter receptors are all targets for altered expression in response to synaptic activity during critical periods. Signaling via BDNF from the pre- to postsynaptic sites is especially important for the modification of gene expression that records activity-dependent change more permanently as transcriptional change. The most accessible and thoroughly studied example of a critical period is that responsible for the establishment of normal vision in mammals, including humans. When typical patterns of activity are disturbed during the critical period in early life (experimentally in animals or by pathology in humans), connectivity in the visual cortex is altered, as is visual function. If not reversed before the end of the critical period, these structural and functional alterations of brain circuitry are difficult or impossible to change. Observations of the addition and elimination of synapses throughout the cerebral cortex in animals, and parallel analysis of the increase and decrease of cortical gray matter volumes where such synapses are made in the brains of children and adolescents, indicate that a full range of human behaviors—including those compromised in conditions such as autism, schizophrenia, and ADHD—may be shaped by activity- and experience-dependent addition and subsequent elimination of synaptic connections during critical periods that begin at birth and end in early adulthood.