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The cerebral cortex is the area of the brain where higher-order cognitive processing occurs. The 2 hemispheres of the cerebral cortex communicate through one of the largest fiber tracts in the brain, the corpus callosum. Malformation of the corpus callosum in human beings occurs in 1 in 4000 live births, and those afflicted experience an extensive range of neurologic disorders, from relatively mild to severe cognitive deficits. Understanding the molecular and cellular processes involved in these disorders would therefore assist in the development of prognostic tools and therapies. During the past 3 decades, mouse models have been used extensively to determine which molecules play a role in the complex regulation of corpus callosum development. This review provides an update on these studies, as well as highlights the value of using mouse models with the goal of developing therapies for human acallosal syndromes.