The Latino population in the United States is increasing rapidly, and Latino youth comprise a significant proportion of the overall school-age population. Latino youth, however, demonstrate lower levels of academic achievement. Research also indicates Latino youth consistently report higher levels of depressive symptoms. We examined the relation between academic achievement and depressive symptoms in Latino youth. We additionally investigated the potential mediating role of academic self-efficacy and goal-orientation as well as the moderating role of acculturative stress. Participants included 133 Latino students enrolled in fifth through seventh grade at an urban public elementary school. Students responded to items about their depressive symptoms, academic self-efficacy, academic orientation, and acculturative stress. Both indicators of academic performance were significantly correlated with depressive symptoms (report card grades r = -0.26, p less than 0.01; standardized test scores r = -0.21, p less than 0.05). As predicted, academic self-efficacy and a performance-avoidance orientation mediated this relationship. Although acculturative stress did not moderate the relationship between achievement and depression, hierarchical regression models revealed that this cultural/contextual variable combined with academic factors to account for 28-32% of the variance in depressive symptoms. We discuss the implications of these findings for clinical intervention and the education system within the US.