Most excitatory synapses in the CNS form on dendritic spines, tiny protrusions from the dendrites of excitatory neurons. As such, spines are likely loci of synaptic plasticity. Spines are dynamic structures, but the functional consequences of dynamic changes in these structures in the mature brain are unclear. Changes in spine density, morphology, and motility have been shown to occur with paradigms that induce synaptic plasticity, as well as altered sensory experience and neuronal activity. These changes potentially lead to an alteration in synaptic connectivity and strength between neuronal partners, affecting the efficacy of synaptic communication. Here, we review the formation and modification of excitatory synapses on dendritic spines as it relates to plasticity in the central nervous system after the initial phase of synaptogenesis. We will also discuss some of the molecular links that have been implicated in both synaptic plasticity and the regulation of spine morphology.