Essential infantile esotropia (EIE) is often attributed to a primary disturbance within the visual cortex based upon the findings of monocular horizontal optokinetic asymmetry and correlative horizontal motion detection asymmetry. However, these physiologic aberrations conform to what would be observed if the visual cortex secondarily reconfigured itself to the preexisting subcortical optokinetic motion template. This analysis examines the perspective that the measured cortical aberrations can be explained by prolonged subcortical neuroplasticity, leading to a secondary rewiring of cortical motion pathways. Evolutionary evidence indicates that EIE is generated by subcortical ocular motor centers that subserve nasalward optokinesis. These phylogenetically older subcortical visuo-vestibular pathways include the nucleus of the optic tract, accessory optic system, inferior olive, cerebellar flocculus, and vestibular nucleus. In normal humans, the subcortical visual system becomes inactivated after the first few months of infancy. Mutations or other perturbations that prolong subcortical neuroplasticity may create a persistent simultaneous nasalward optokinetic bias in both eyes to generate infantile esotropia.