Poverty increases maternal stress by heightening exposure to negative life events, job loss, chronic strains, poor housing, dangerous neighborhoods, and conflict with partners, culminating in crippling depressive symptoms, the most prevalent mental health threat. Depressive symptoms interfere with the provision of the strong maternal support needed to counter the hardships of poverty, thus placing infants and toddlers at risk for delayed language, social, and emotional development. Initial clinical trials in high-risk mothers have shown promise, and successive tests of interventions will be strengthened if mothers who have mental health risks can be accurately targeted for inclusion. This article reports on a sequential, data-driven process by which high-risk mothers were targeted for intervention in two trials currently in progress to reduce depressive symptoms. An iterative process of using data to identify at-risk mothers and validate the presence of risk factors helped hone the recruitment and design of the intervention trials. This report also offers guidance for further study.