Molecular epidemiological studies are now a powerful tool to determine differential genetic susceptibilities to cancer-causing agents, and to obtain information on potential mechanisms. Cytochrome P450 (CYP) allelic variants are considered biomarkers of susceptibility to cancer. Such variants have an influence on the bioactivation and thereby on the potency of chemical carcinogens. This is very much straight forward for tobacco smoke-related human cancers. A new aspect is the implication of CYP1B1 in tobacco smoke-related cancers at several organ sites. On this basis, the present review is focused on lung, breast, urinary bladder and head and neck cancer. The CYP profile of the human lung includes CYP1A1, -1B1, -2A6, -2A13, -2B6, -2C18, -2E1, -2F1, -3A5 and -4B1. Polycyclic aromatic hydrocarbons (PAHs) and nitrosamines, as active components of tobacco smoke, appear as primary chemical factors for lung malignancies. For human mammary cancer, the use of hormone replacement therapy (HRT) has been shown to be associated with an increase of breast cancer risk, and there seems to be a link between risks caused by HRT use and modifying polymorphisms of drug/xenobiotic enzymes. Specifically, an association of the CYP1B1*3/*3 genotype with increased breast cancer risks has been postulated. Cigarette smoking is a major cause of human urinary bladder cancer. Arylamines, PAHs and nitrosamines are locally activated within the urothelium. Important CYPs in the bladder epithelium of experimental animals and man are CYP1B1 and -4B1. Alcohol consumption and tobacco smoking are known as the major causes of head and neck cancers. Recently, it appears that a polymorphic variant CYP1B1*3/*3 relates significantly to the individual susceptibility of smokers to head and neck cancer, supporting the view that PAH are metabolically activated through CYP1B1. It appears that CYP1B1 plays a key role for the activation of carcinogens at several organ targets, with a likelihood of complex gene-environment interactions implying Phase II enzymes.