The ability to efficiently store memories in the brain is a fundamental process and its impairment is associated with multiple human mental disorders. Evidence indicates that long-term memory (LTM) formation involves alterations of synaptic efficacy produced by modifications in neural transmission and morphology. The actin cytoskeleton has been shown to be involved in these key neuronal processes by subserving events such as presynaptic vesicle movement, postsynaptic glutamate receptors trafficking and dendritic spines morphogenesis. Actin cytoskeleton dynamics and structure underlying such cellular events can be regulated by extracellular signals through its regulatory proteins. Recent findings show that the actin cytoskeleton and its regulatory proteins are needed for memory formation and extinction in different organisms throughout the phyla from invertebrates such as Caenorhabditis elegans and Drosophila to mammalians. The actin cytoskeleton and its regulatory proteins participate in the formation of various types of memories that are subserved by different neurons and brain regions. The actin cytoskeleton may therefore mediate between synaptic transmission during learning and long-term cellular alterations mandatory for memory formation.