This study investigated whether chronic adolescent social stress, genetic background, and their interaction influence later morphine sensitivity and sensitization. Our data show that genetic background alters morphine responses such that C57BL/6J mice developed a sensitized response to morphine, but BALB/cJ mice did not. Further, in C57BL/6J mice, adolescent social stress attenuated morphine sensitization. Our findings suggest that adolescent stress interacts with genetic background to alter behaviors related to opioid dependence.