Throughout history, many scientists have wondered about the reason for neural pathway decussation in the CNS resulting in contralateral forebrain organization. Hitherto, one of the most accepted theories is the one described by the renowned Spanish physician, Santiago Rámon y Cajal at the end of the 19th century. This Nobel Prize winner, among his many contributions to science, gave us the answer to this question: the key lies in the optic chiasm. Based on the fact that the ocular lenses invert the image formed in the retina, Cajal explained how the decussation of the fibers in the optic chiasm is necessary to obtain a continuous image of the outside in the brain. The crossing of the tactile and motor pathways occurred posteriorly as a compensatory mechanism to allow the cortical integration of the sensory, motor, and visual functions. This theory had a great influence on the scientific community of his time, and maintains its importance today, in which none of the theories formulated to date has managed to entirely refute Cajal’s. In addition, the decussation of neural pathways plays a significant role in different diseases, especially in the recovery process after a hemispheric lesion and in several congenital pathologies. The advantages of cerebral lateralization have also recently been published, although the evolutionary connection between fiber decussation and cortical function lateralization remains a mystery to be solved. A better understanding of the molecular and genetic substrates of the midline crossing processes might result in significant clinical advances in brain plasticity and repair.