Depression and college stress, major concerns among undergraduates, are potentially related to self-esteem and mattering. This study investigated the interrelationships among these four variables. Participants included college students (199 males and 256 females) between the ages of 18 and 23. Significant sex differences were found with women reporting greater depression, college stress, and mattering. Sex, self-esteem, and mattering accounted for 13.8% and 39.4% of the variance in stress and depression, respectively. Accounting for 49.1% of the variance, the full model including sex, self-esteem, and mattering enhanced the ability of stress to predict depression. All of the study hypotheses were supported. (Contains 2 tables.)