Heterocyclic amines (HAs) formed during the cooking of meat require metabolic activation before they are genotoxic. In most species, this is catalyzed predominantly by CYP1A2. As this enzyme is expressed almost exclusively in the liver, this coupled with differences in the metabolic and chemical stability of the N-hydroxy metabolites, is a major determinant of the target organ specificity of HAs. Although CYP1A2 is responsible for HA activation in most species, metabolic specificity can vary quite markedly. For example, N-hydroxylation is the only significant pathway of HA oxidation in man, whereas in rodents competing ring-oxidation reactions occur. Activation will also depend upon the catalytic efficiency of CYP1A2 towards HAs. Human CYP1A2 shows similar kinetics in the N-hydroxylation of different HAs. Rat CYP1A2 is less effective at activating most HAs compared with the human enzyme. The level of CYP1A2 expression is an important determinant of HA activity. In humans, variation in such expression is a major factor in determining interindividual differences in HA activation. The importance of CYP1A2 expression is evident from the resistance of the cynomolgus money, a species in which there is no constitutive expression of CYP1A2, to the tumorigenicity of most HAs. Although exposure to inducing agents such as cigarette smoke increases CYP1A2 expression, the net effect on HA activity appears to depend upon the balance between increased activation and increased detoxication. There are epidemiological data to support this.