SummaryIndividuals born without one hand (congenital one-handers) provide a unique model for understanding the relationship between focal reorganization in the sensorimotor cortex and everyday behavior. We previously reported that the missing hand’s territory of one-handers becomes utilized by its cortical neighbor (residual arm representation), depending on residual arm usage in daily life to substitute for the missing hand’s function [1, 2]. However, the repertoire of compensatory behaviors may involve utilization of other body parts that do not cortically neighbor the hand territory. Accordingly, the pattern of brain reorganization may be more extensive [3]. Here we studied unconstrained compensatory strategies under ecological conditions in one-handers, as well as changes in activation, connectivity, and neurochemical profile in their missing hand’s cortical territory. We found that compensatory behaviors in one-handers involved multiple body parts (residual arm, lips, and feet). This diversified compensatory profile was associated with large-scale cortical reorganization, regardless of cortical proximity to the hand territory. Representations of those body parts used to substitute hand function all mapped onto the cortical territory of the missing hand, as evidenced by task-based and resting-state fMRI. The missing-hand territory also exhibited reduced GABA levels, suggesting a reduction in connectional selectivity to enable the expression of diverse cortical inputs. Because the same body parts used for compensatory purposes are those showing increased representation in the missing hand’s territory, we suggest that the typical hand territory may not necessarily represent the hand per se, but rather any other body part that shares the functionality of the missing hand [4].