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Inhibition of steroidogenic enzymes, which are involved in the biosynthesis of active estrogens, represents an attractive approach to treating hormone-dependent breast cancer. Synthetic routes to novel steroid-based inhibitors of two key enzymes, steroid sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD type 1), are described. Biological evaluation of the derivatives in vitro indicated that most of the compounds synthesised were active against the selected targets to varying degrees. Particular attention was given to assessing the estrogenicity of potential inhibitors, since agonist activity at the estrogen receptor is undesired in the treatment of estrogen-dependent pathologies. Modifications to the D-ring of estrone-3-O-sulfamate EMATE, a potent STS inhibitor, successfully afforded a 3-sulfamoyloxy-16,17-seco-estra-l,3,5(10)-triene16,17-imide template, from which a series of N-alkylated analogues were prepared. The N-propyl and N-pyridin-3-ylmethyl derivatives were 18 times more potent than EMATE in vitro, with IC50S of 1 nM in placental microsomes. In vivo, these compounds inhibited 99% of rat liver sulfatase activity at an oral dose of 10 mg/kg. Importantly, they were also devoid of estrogenic activity. The SAR for the derivatives synthesised is discussed and a QSAR was established. Substrate-based design of 17β-HSD type 1 inhibitors resulted in the identification of several lead compounds, mostly D-ring modified estrogens. The potential of 16-alkylidenes derivatives of estradiol as enzyme-generated irreversible inhibitors was examined. Small modifications to the estra-l,3,5(10)-triene nucleus were investigated. Both studies were assisted by molecular modelling, using the crystal structure of the enzyme. D-Ring fused heterocyclic derivatives of estrone were prepared and an SAR was built around N-alkylated 16,17-fused pyrazoles. The Nethoxymethyl derivative emerged as a potent inhibitor of 17β-HSD type 1 in vitro without being estrogenic. A preliminary study focused on the design of dual inhibitors of STS and 17P-HSD type 1 is also reported here. The synthetic work was supported by single crystal X-ray analyses.