Steroid sulfatase (STS) catalyzes the desulfation of biologically inactive sulfated steroids to yield biologically active desulfated steroids and is currently being examined as a target for therapeutic intervention for the treatment of breast and other steroid-dependent cancers. Here we report the synthesis of a series of 17b-arylsulfonamides of 17b-aminoestra-1,3,5(10)-trien-3-ol and their evaluation as inhibitors of STS. Some of these compounds are among the most potent reversible STS inhibitors reported to date. Introducing n-alkyl groups into the 40-position of the 17b-benzenesulfonamide derivative resulted in an increase in potency with the n-butyl derivative exhibiting the best potency with an IC50 of 26 nM. A further increase in carbon units (to n-pentyl) resulted in a decrease in potency. Branching of the 40-n-propyl group resulted in a decrease in potency while branching of the 40-n-butyl group (to a tert-butyl group) resulted in a slight increase in potency (IC50 = 18 nM). Studies with 30- and 40-substituted substituted 17b-benzenesulfonamides with small electron donating and electron withdrawing groups revealed the 30-bromo and 30-trifluoromethyl derivatives to be excellent inhibitors with IC50’s of 30 and 23 nM, respectively. The 17b-20-naphthalenesulfonamide was also an excellent inhibitor (IC50 = 20 nM) while the 17b-40-phenylbenzenesulfonamide derivative was the most potent inhibitor of all the compounds studied with an IC50 of 9 nM.