In this study, the effects of peer acceptance and rejection on global self-esteem and emotional school engagement in adolescents were investigated. Moreover, in line with the differential susceptibility hypothesis, we examined the potential moderating effect of a polymorphism in the serotonin receptor gene (i.e., 5-HTTLPR). The sample consisted of 1,111 Flemish adolescents (49% girls; M[superscript age] = 13.79, SD = 0.94) in Grades 7-9. Self-report questionnaires, peer nominations, and saliva sampling were used to collect data. Peer rejection was associated with lower global self-esteem and less emotional school engagement. Contrary to our hypotheses, peer acceptance was not associated with emotional school engagement or global self-esteem. In addition, no significant moderating effects were found. These results indicate that only the negative experience of peer rejection plays a role in adolescents' self-esteem and emotional school engagement. Implications and suggestions for future research are discussed.