The atomic-resolution crystal structures of human carbonic anhydrases I and I I complexed with "two-prong" inhibitors are reported. Each inhibitor contains a benzenesulfonamide prong and a cupric iminodiacetate (IDA-Cu2+) prong separated by linkers of different lengths and compositions. The ionized NH- group of each benzenesulfonamide coordinates to the active site Zn2+ ion; the IDA-Cu2+ prong of the tightest-binding inhibitor, BR30, binds to H64 of CAII and H200 of CAI. This work provides the first evidence verifying the structural basis of nanomolar affinity measured for two-prong inhibitors targeting the carbonic anhydrases.