Background: Research examining intergenerational transmission of psychopathology is often limited by reliance on the same individuals for information on multiple constructs of interest. To counteract this limitation, data from a prospective, longitudinal study of at-risk youth were analyzed to test the hypothesis that parenting and family environmental factors mediate the association between maternal depressive symptoms and offspring psychopathology in late adolescence. Method: Data were taken from 184 families of the Minnesota Longitudinal Study of Parents and Children. Measures included the CES-D and Beck depression inventories, home environment ratings and a family conflict scale, and CBCL behavior problem checklist and K-SADS psychiatric symptom scores. Regression analyses were conducted to test for mediation of maternal depression effects by family environmental factors. Results: Analyses using a single informant and time point showed evidence for substantial mediation; however, in analyses spanning independent informants and multiple time points mediating effects were markedly reduced. Sex differences were found, in that parenting and family environmental factors related to psychopathology for males, whereas maternal depression was more directly related to psychopathology for females. Conclusions: Results emphasize the importance of independent data for testing mediational claims, and support claims that the processes involved in the intergenerational transmission of psychopathology are different for male and female youth.