Recent functional imaging studies of topographical learning point to the participation of a large network of cortical and subcortical regions. Nevertheless, areas which are crucial remain poorly specified due to the absence of group studies of subjects with focal lesions distributed throughout the brain. We assessed the ability of 127 subjects with stable, focal lesions to learn a complex real-life route, a critical aspect of topographical functioning. Results indicated that impairment in route learning was highly associated with damage to medial occipital and posterior parahippocampal cortices in either hemisphere, the right hippocampus, and the right inferotemporal region. Impairment was seen among 86% of the subjects with damage to any these regions, in contrast to impairment among 31% of subjects with lesions in other regions. The importance of medial occipitotemporal cortices bilaterally and right inferotemporal cortex likely reflects the critical role of the ability to quickly and accurately perceive and learn multiple topographical scenes. The importance of the right (and probably left) posterior parahippocampal gyrus and of the right hippocampus likely reflects their critical, distinctive roles forming an integrated representation of the extended topographical environment (i.e., the appearance of places and spatial relationships between specific places), and consolidating that representation into multifaceted contextual knowledge of the environment.