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The human cytochrome P450 (CYP) 1A1 gene encodes a monooxygenase that metabolizes multiple exogenous and endogenous substrates. CYP1A1 has become infamous for its oxidative metabolism of benzo[a]pyrene and related polycyclic aromatic hydrocarbons, converting these chemicals into very potent human carcinogens. CYP1A1 expression is mainly controlled by the aryl hydrocarbon receptor (AHR), a transcription factor whose activation is induced by binding of persistent organic pollutants, including polycyclic aromatic hydrocarbons and dioxins. Accordingly, induction of CYP1A1 expression and activity serves as a biomarker of AHR activation and associated xenobiotic metabolism as well as toxicity in diverse animal species and humans. Determination of CYP1A1 activity is integrated into modern toxicological concepts and testing guidelines, emphasizing the tremendous importance of this enzyme for risk assessment and regulation of chemicals. Further, CYP1A1 serves as a molecular target for chemoprevention of chemical carcinogenesis, although present literature is controversial on whether its inhibition or induction exerts beneficial effects. Regarding therapeutic applications, first anti-cancer prodrugs are available, which require a metabolic activation by CYP1A1, and thus enable a specific elimination of CYP1A1-positive tumors. However, the application range of these drugs may be limited due to the frequently observed downregulation of CYP1A1 in various human cancers, probably leading to a reduced metabolism of endogenous AHR ligands and a sustained activation of AHR and associated tumor-promoting responses. We here summarize the current knowledge on CYP1A1 as a key player in the metabolism of exogenous and endogenous substrates and as a promising target molecule for prevention and treatment of human malignancies.