Although there have been advances in our ability to treat child and adolescent depression, use of evidence-based treatments still results in many patients with residual symptoms. Advances in our understanding of cognitive, emotional, and ecological aspects of early-onset depression have the potential to lead to improvements in the assessment and treatment of depression. A search for endophenotypes, i.e., traits that are related to depression, mediate the familial transmission of depression, and are genetically determined, may help in understanding etiology and in personalizing treatment. However, advances in treatment may also come from the identification of biomarkers, i.e., modifiable neurocognitive, physiological, or biochemical indices that are correlated with, or mediate, treatment outcome. More effective treatments may emerge from being able to personalize interventions to the patient's cognitive, emotional, and developmental profile.