The thalamocortical (TC) projection in the mammalian brain involves fundamental aspects in branch formation during development. TC axons are known to form branches not only in a genetically defined but also in an activity-dependent fashion. Recent evidence indicates that TC axon branching is generated by positive and negative regulators that are expressed with laminar specificity in the developing cortex. Moreover, in vitro studies using organotypic cocultures demonstrate that neural activity, including firing and synaptic activity, controls lamina-specific TC axon branching by altering its remodeling process with addition and elimination. Taken together, activity-dependent mechanisms can contribute to branch formation, affecting expression of branch-promoting and inhibiting factors and/or their receptor molecules.