The long-sleep (LS) and short-sleep (SS) mouse lines were selectively bred for differential sensitivity to the anesthetic actions of ethanol, but they also differ in sensitivity to nicotine. A recent study suggested that the LS mice develop more tolerance to ethanol and cross-tolerance to nicotine than do the SS following chronic ethanol treatment. The studies reported here expand on these previous studies by assessing potential tolerance to ethanol and cross-tolerance to nicotine using additional behavioral and physiological measures. In addition, the effects of chronic ethanol treatment on ethanol and nicotine metabolism were measured. The LS mice developed tolerance to ethanol as measured by effects on open-field activity, body temperature, and sleep time, whereas the SS mice did not develop consistent tolerance to ethanol's effects on any of these measures. Cross-tolerance to nicotine's effects on open-field activity and body temperature developed, but only in the LS mice. The ethanol tolerance is likely due to changes in CNS sensitivity to ethanol, but altered elimination of nicotine may explain much of the cross-tolerance to nicotine seen in chronic ethanol-treated LS mice.