The two major causes of bladder cancer, cigarette smoking and occupational exposure to arylamines, have been recognized for 4 decades. Recently, attention has turned increasingly toward molecular approaches that can help predict which individuals exposed to these factors are at greatest risk of developing bladder cancer and can help explain the wide variation in bladder cancer risk among populations with similar prevalences of exposure to these two known causes. The mechanism for the relationship between smoking and bladder cancer risk has not yet been fully elucidated, but most likely is due to the presence in cigarette smoke of low levels of the same carcinogenic arylamines known to induce bladder cancer in occupational settings. These arylamines undergo metabolic transformation and the activated forms can form adducts with DNA, a probable essential step in the carcinogenic process. Alternatively, these arylamines can be detoxified. Two of the enzymes involved in this detoxification, glutathione S transferase mu and N-acetyltransferase, are genetically controlled. There is now ample epidemiological evidence that variations in the genes that code for these enzymes can affect bladder cancer risk among individuals exposed to arylamines. Levels of arylamine adducts are strongly correlated with cigarette "dose" and can be substantially modified by these detoxifying enzymes.