There is strong evidence that family factors play a role in the development, maintenance and course of youth depression. However, to date few clinical trials of psychotherapy for youth depression employ family therapy interventions or target the known family risk factors. This is surprising given recent meta-analytic findings showing only modest effect sizes for psychotherapy for youth depression, and that cognitive therapies do not outperform non-cognitive therapies. The aim of this review is to I) use a developmental systems approach to review empirical evidence on family risk factors for youth depression to identify potential targets for treatment. 2) examine the extent to which these family risk factors have been targeted in clinical trials for youth depression, and 3) provide a road map for the development of empirically validated family-based interventions for youth depression. Strong evidence was found supporting a relationship between family factors at multiple system levels and depressive symptoms or disorders. Support for several different hypothesized causal mechanisms as well as bidirectional effects was found. A comparison of the identified risk factors and psychotherapy trials for youth depression indicated that few RCT's target family factors; among those that do, only a few of the family risk factors are targeted. Recommendations for translation of empirical knowledge of family risk factors and mechanisms to develop empirically valid family-based interventions to enhance existing treatments for youth depression are provided.