Spine morphogenesis is largely dependent on the remodeling of the actin cytoskeleton. Actin dynamics within spines is regulated by a complex network of signaling molecules, which relay signals from synaptic receptors, through small GTPases and their regulators, to actin-binding proteins. In this chapter, we will discuss molecules involved in dendritic spine plasticity beginning with actin and moving upstream toward neuromodulators and trophic factors that initiate signaling involved in these plasticity events. We will place special emphasis on small GTPase pathways, as they have an established importance in dendritic spine plasticity and pathology. Finally, we will discuss some epigenetic mechanisms that control spine morphogenesis.