AKR1C4 is a hepatic cytosolic aldo-keto reductase that catalyzes NADPH-dependent reduction of ketosteroids to hydroxysteroids with broad substrate specificity. The enzyme plays critical roles in steroid hormone metabolism: it is required for male sex determination through the 'backdoor' androgen biosynthesis pathway, generating 5α-dihydrotestosterone via conversion of 5α-dihydroprogesterone to allopregnanolone, and acts together with AKR1C2 to promote embryonic testis differentiation. AKR1C4 also regulates circulating neurosteroid concentrations by reducing precursors to neuroactive steroids including allopregnanolone, which modulates neural excitability via GABA(A) receptor activation. The enzyme inactivates active sex hormones by converting 5α-DHT and progesterone into their respective metabolites, and participates in androgen catabolism as both a phase I and phase II metabolic enzyme. Additionally, AKR1C4 catalyzes biotransformation of the pesticide chlordecone to reduce its neurotoxicity. Disease associations include 46,XY disorders of sex development and altered neurosteroid metabolism linked to bipolar disorder 1 and paranoid ideation 2. A low-frequency AKR1C4 variant (10p15 locus) was associated with age at menarche in African-ancestry women 3. In breast cancer among the Bangladeshi population, the rs17134592 polymorphism carrying the GG genotype increased breast cancer risk, particularly in post-menopausal women 4. AKR1C4 expression was an independent prognostic factor for locoregional recurrence in nasopharyngeal carcinoma 5. The enzyme represents an emerging target for hormone-dependent cancers and neuropsychiatric disorders 6.