Drawing from insights from communication science and behavioral economics, the University of Pennsylvania Telehealth Research Center of Excellence (Penn TRACE) is designing and testing telehealth strategies with the potential to transform access to care, care quality, outcomes, health equity, and health-care efficiency across the cancer care continuum, with an emphasis on understanding mechanisms of action. Penn TRACE uses lung cancer care as an exemplar model for telehealth across the care continuum, from screening to treatment to survivorship. We bring together a diverse and interdisciplinary team of international experts and incorporate rapid-cycle approaches and mixed methods evaluation in all center projects. Our initiatives include a pragmatic sequential multiple assignment randomized trial to compare the effectiveness of telehealth strategies to increase shared decision-making for lung cancer screening and 2 pilot projects to test the effectiveness of telehealth to improve cancer care, identify multilevel mechanisms of action, and lay the foundation for future pragmatic trials. Penn TRACE aims to produce new fundamental knowledge and advance telehealth science in cancer care at Penn and nationally.