Dehydrogenase-17β-hydroxysteroid-type-5, one of the eight types of 17β-hydroxysteroid dehydrogenase so far characterized in humans, catalyzes the NADPH dependent stereospecific reduction of carbonyl moieties on substrates of importance to the pre-receptor regulation of signaling pathways involved in cell proliferation. Also known as AKR1C3, it reduces 4 androstene-3,17-dione (a weak androgen) to form testosterone (a potent androgen) and estrone (a weak estrogen) to form 17β-estradiol (a potent estrogen), leading to trans-activation of the androgen and estrogen receptors, respectively. There are three other closely related enzyme isoforms, AKR1C1, AKR1C2, and AKR1C4, which share greater than 84% sequence homology with AKR1C3 and are also involved in steroid hormone metabolism. AKR1C3 inhibition is desirable for hormone dependent and independent cancers NSAIDs, steroids, flavonoids, cyclopentanes, and benzodiazepines inhibit AKR1C3. Crystal structures identify subpockets for rational design of AKR1C3 inhibitors. Differences in AKR1C subpockets can be exploited for selective inhibition [1].