Patients with multiple psychiatric and medical comorbidities are common in primary care practices (PCPs), and recent health care reforms will likely lead to an increase in their numbers. PCPs need flexible, integrated mental health–primary care interventions that are applicable to these complex patients and compatible with the PCP setting. Generating practice-ready solutions for rapid uptake in typical PCPs requires a new direction for mental health–primary care research. This column describes an approach that embraces both real-world relevance and methodological rigor to stimulate such research. The approach emphasizes generating knowledge that decision makers need, using practice-based evidence and efficient methods, and planning for sustainability and broad uptake from the outset.