By adulthood, literate humans have been exposed to millions of visual scenes and pages of text. Does the human visual system become attuned to the statistics of its inputs? Using functional magnetic resonance imaging, we examined whether the brain responses to line configurations are proportional to their natural-scene frequency. To further distinguish prior cortical competence from adaptation induced by learning to read, we manipulated whether the selected configurations formed letters and whether they were presented on the horizontal meridian, the familiar location where words usually appear, or on the vertical meridian. While no natural-scene frequency effect was observed, we observed letter-status and letter frequency effects on bilateral occipital activation, mainly for horizontal stimuli. The findings suggest a reorganization of the visual pathway resulting from reading acquisition under genetic and connectional constraints. Even early retinotopic areas showed a stronger response to letters than to rotated versions of the same shapes, suggesting an early visual tuning to large visual features such as letters.