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Single agents against multiple drug targets are highly topical. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS), and several dual aromatase-sulfatase inhibitors (DASIs) have been recently reported. The best compounds from two leading classes of DASI, 3 and 9, are low nanomolar inhibitors. In search of a novel class of DASI, core motifs of two leading classes were combined to give a series of hybrid structures, with several compounds showing markedly improved dual inhibitory activities in the picomolar range in JEG-3 cells. Thus, DASIs 14 (IC50: aromatase, 15 pM; STS, 830 pM) and 15 (IC50: aromatase, 18 pM; STS, 130 pM) are the first examples of an exceptional new class of highly potent dual inhibitor that should encourage further development toward multitargeted therapeutic intervention in HDBC.