Alterations in the activity of one sensory system can affect the development of cortical and subcortical structures in all sensory systems. In this study, we characterize the changes that occur in visual and nonvisual areas of the brain following bilateral enucleation in short-tailed opossums. We demonstrate that bilateral enucleation early in development can significantly decrease brain size. This change is driven primarily by a decrease in the size of the thalamus, midbrain, and hindbrain, rather than a decrease in the size of the cortical hemispheres. We also found a significant decrease in the size of the lateral geniculate nucleus in bilaterally enucleated animals. Although the overall size of the neocortex was the same, the percentage of neocortex devoted to visual areas V1 (primary visual area) and caudotemporal area were significantly smaller in bilaterally enucleated opossums and the percentage of neocortex devoted to the primary somatosensory area (S1) was significantly larger, although S1 did not change in size to the same extent as V1. Our data suggest that during development the relative activity patterns between sensory systems, which are driven by activity from unique sets of sensory receptor arrays, play a major role in determining the relative size and organization of cortical and subcortical areas.