Among inbred mice from the high-leukemia strain AKR and the low-leukemia strain Af, which in addition represent extremes of resistance and susceptibility, respectively, to polycyclic hydrocarbon-induced skin tumorigenesis, marked cell- and tissue-specific differences were apparent in the capability of aryl hydrocarbon hydroxylase activity to be induced in response to 3-methylcholanthrene (MCA). In Af mice, aryl hydrocarbon hydroxylase was inducible by twofold to severalfold in most tissues examined, except possibly some lymphoreticular organs, e.g., spleen. In AKR mice, however, this enzyme system in liver was relatively resistant to induction by MCA. In contrast, the extrahepatic hydroxylase activity from AKR mice was slightly induced in tissues such as lung, epidermis, and probably lymph nodes. The F1 hybrid mice from genetic crosses between these strains resembled Af mice in susceptibility to the effects of MCA as inducer of hydroxylase activity in most tissues tested, though not to the same degree as the parent inbred strain. Further, these hybrids lack MCA-inducible enzyme in corium cutis under the experimental conditions. Thus the regulation of enzyme induction, in the genetic groups examined, seemed not to reflect simple mendelian genetics. The control and inducible levels of hepatic hydroxylase activity from inbred and hybrid mice were higher in females than in males. The hepatic enzyme system derived from female mice was more active in metabolizing MCA as substrate and in catalyzing the formation of polycyclic hydrocarbon-hepatic cytosol protein complexes. However, a lack of correlation was noted between metabolism of MCA or binding of polycyclic hydrocarbon to cytosol macromolecules and the ability of hepatic hydroxylase activity to be induced in response to MCA.