The role of initial sensitivity and genetic factors in the development of tolerance to ethanol were examined in rats selected for low (AT) and high (ANT) sensitivity to the motor impairment effect of ethanol. Following chronic ethanol treatment (5 g/kg PO, daily for 20 days), the AT and ANT rats acquired tolerance to the motor impairment effect of ethanol at a similar rate. The AT rats, however, acquired tolerance to the hypothermic effect of ethanol at a higher rate than the ANT rats. Such ethanol treatment did not produce any metabolic tolerance to ethanol in these animals. Since there is no difference in the initial response to the hypothermic effect of ethanol between the AT and ANT rats, the observed differences in the rate of tolerance development might be related to a direct genetic factor. The similar rate of tolerance development to the motor impairment effect of ethanol between the two lines was attributed to an interaction between an indirect (initial sensitivity) and a genetic factor in tolerance development.