Mitogen-activated protein kinases (MAPKs) are expressed in postmitotic neurons and act as important regulators in intracellular signaling. In addition to their nuclear distribution and roles in regulating gene expression, MAPKs, especially the extracellular signal-regulated kinase (ERK) subclass, reside in peripheral dendritic spines and synapses, including the postsynaptic density (PSD) microdomain. This peripheral pool of MAPKs/ERKs is either constitutively active or sensitive to changing synaptic input. Active MAPKs directly interact with and phosphorylate local substrates to alter their trafficking and subcellular/subsynaptic distributions, through which MAPKs regulate function of substrates and contribute to long-lasting synaptic plasticity. A number of physiologically relevant substrates of MAPKs have been identified at synaptic sites. Central among them are key synaptic scaffold proteins (PSD-95 and PSD-93), cadherin-associated proteins (delta-catenin), Kv4.2 K+ channels, and metabotropic glutamate receptors. Through a reversible phosphorylation event, MAPKs rapidly and efficiently modulate the function of these substrates and thus determine the strength of synaptic transmission. This review summarizes the recent progress in cell biology of synaptic MAPKs and analyzes roles of this specific pool of MAPKs in regulating local substrates and synaptic plasticity.