Interhemispheric axon fibers connect the two cerebral cortical hemispheres via the corpus callosum and function to integrate information between the hemispheres. In the development of callosal connections, an early phase involves axon guidance molecules and a later phase requires neuronal activity. In addition to the well-studied role of sensory-driven neuronal activity, recent studies have demonstrated an essential role of callosal neuron firing activity in forming axonal projections and dendritic maturation during the developmental period before sensory input is available. Results suggest that factors affecting the cellular excitability of developing callosal neurons can influence the establishment of interhemispheric connections. Possible synaptic and non-synaptic mechanisms for activity-dependent axonal projections are discussed.