The steroid sulfatase (STS) enzyme plays a pivotal role in the formation of biologically active steroid hormones. Its involvement in the hydrolysis of estrone sulfate and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone, respectively, is an important step in the formation of estradiol and androstenediol, both of which are estrogenic steroids that can stimulate tumor growth. Consequently, as STS is widely distributed throughout the entire body, it has a substantial influence on hormone-dependent cancer mitogenesis. It is a useful prognostic marker of disease as a significant majority of breast tumors over-express the enzyme and there are indications of STS having a role in prostate cancer. This knowledge has led to the development of potent STS inhibitors for use as anti-cancer agents. There are now several steroidal and non-steroidal STS inhibitors available. New in vivo models, using ovariectomized female nude mice, have been developed to pre-clinically test these inhibitors. These studies have demonstrated the excellent efficacy and effect of STS inhibitors on breast carcinoma development. Recently, 667 COUMATE, an irreversible type of inhibitor which utilizes a phenol sulfamate ester as its active pharmacophore, has completed a Phase I clinical trial in postmenopausal women with breast cancer. These studies have indicated the potential clinical benefit for the use of STS inhibitors. Most pre-clinical and clinical studies have focused on breast cancer as the target for STS inhibition. However, there are other hormone-dependent malignancies, such as endometrial and prostate cancer, that could in the future be treated with these new potent STS inhibitors.