This article is about the discovery and development of 5α-reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers. Development of 5α-reductase inhibitors These are two types of 5-ARIs, categorized as steroidal and nonsteroidal 5-ARIs. Steroidal 5α-reductase inhibitors Steroid 5α-reductase is a membrane-associated enzyme in an oxidoreductase family and has an important role in biological actions towards steroid metabolism. If the steroid 5α-reductase is overexpressed it causes overproduction of DHT that can lead to androgenic disorders in humans. The 5α-reductase isozymes possess a similar steroidal catalytic site. The only available information about the 5α-reductase isozymes is their primary sequence estimated from c-DNAs and that affects the design of the novel inhibitors. The crystal structure of the 5α-reductase isozymes is not known because the nature of the 5α-reductase enzyme is so unstable during purification. The first 5-ARIs were designed by modifying the structure of natural substrates, including the substitution of one carbon atom of the rings of the steroids by a heteroatom such as nitrogen thereby forming azasteroids. The receptor is known to consist of two hydrogen bond donors, where the C3 and 17β-side chain of the ligands connect, as well as three hydrophobic groups distributed over the steroidal structure. The best receptor inhibitors comply with these factors. Azasteroids are a type of steroid derivatives which have nitrogen atoms replaced at various positions for one of the carbon atoms in the steroid ring system. Two 4-azasteroids, finasteride and dutasteride are marketed as 5-ARIs. Finasteride (Proscar or Propecia) was the first steroidal 5α-reductase inhibitor approved by the U.S. Food and Drug Administration (USFDA). It inhibits the function of two of the isoenzymes (type II and III). In human it decreases the prostatic DHT level by 70–90% and reduces the prostatic size. Dutasteride (Avodart) was the second steroidal 5α-reductase approved after finasteride. It is a competitive inhibitor of all three 5α-reductase isoenzymes and it inhibits types 1 and 2 better than finasteride, leading to it causing further reduction in DHT, with >90% recuded DHT levels following 1 year of oral administration. Epristeride is the third marketed steroidal 5-ARI. It is a noncompetitive, specific inhibitor. It potency is not as significant as finasteride or dutasteride and thus it is only marketed in China. Nonsteroidal 5α-reductase inhibitors Various pharmaceutical and academic groups have conducted the synthesis of nonsteroidal compounds that inhibit human 5α-reductases due to the unwanted hormonal side effects of steroidal compounds. Nonsteroidal inhibitors can