Human carbonic anhydrase IX (CA IX) is highly expressed in tumor tissues and its selective inhibition provides potential target for treatment against numerous cancers. Development of potent, highly selective inhibitors against this target remains an unmet need in anti-cancer therapeutics. A series of fluorinated benzenesulfonamides with substituents on the benzene ring were designed and synthesized. Several of these exhibited a highly potent and selective inhibition profile against CA IX. Three fluorine atoms significantly increased the affinity by withdrawing electrons and lowering the pKa of the benzene sulfonamide group. The bulky ortho substituents such as cyclooctyl or even cyclododecyl groups fit to the hydrophobic pocket in the active site of CA IX but not CA II, as shown by the compound cocrystal structure with the chimeric CA IX. The strongest inhibitor of recombinant human CA IX catalytic domain produced in human cells achieved the affinity of 50 pM. However, the high affinity diminished the selectivity. The most selective compound for CA IX exhibited 10 nM affinity. The compound which showed the best balance between affinity and selectivity properties bound with 1 nM affinity. The inhibitors described in this work provide the basis for novel anticancer therapeutics targeting CA IX.