Cancer genome sequencing has shown that driver genes can often be distinguished not only by the elevated mutation frequency but also by specific nucleotide positions that accumulate changes at a high rate. However， properties associated with a residue's potential to drive tumorigenesis when mutated have not yet been systematically investigated. Here， using a novel methodological approach， we identify and characterize a compendium of 180 hotspot residues within 160 human proteins which occur with a significant frequency and are likely to have functionally relevant impact. We find that such mutations (i) are more prominent in proteins that can exist in the on and off state， (ii) reflect the identity of a tumor of origin， and (iii) often localize within interfaces which mediate interactions with other proteins or ligands. Following， we further examine structural data for human protein complexes and identify a number of additional protein interfaces that accumulate cancer mutations at a high rate. Jointly， these analyses suggest that disruption and dysregulation of protein interactions can be instrumental in switching functions of cancer proteins and activating downstream changes.