Abstract Background: Patient navigation for breast cancer seeks to diminish social, economic, cultural and medical system barriers to timely quality care. In the context of unmet patient needs, growing complexity of health care delivery systems, and significant local implementation challenges, patient navigation models must continue to evolve in order to advance context-appropriate implementation and sustainment of patient navigation into routine practice. We present five case studies in Chicago demonstrating evolving patient navigation models and in each case study, we explore challenges and opportunities related to advancing successful implementation of patient navigation interventions across the breast cancer care continuum. Methods: Case studies include: (1) a community-level adaptation of patient navigation in Chicago's Chinatown; (2) a community navigation program in Chicago's racially/ethnically diverse North Lawndale and Humboldt Park; (3) a county-wide dissemination of navigation in suburban DuPage County; (4) a state-wide scaling of a patient navigation model to the Illinois Department of Health and Family Services; and (5) a 4R patient navigation oncology model (4R = Right Information / Care / Patient / Time) grounded in systems engineering and design that leverages collaborative care plans and iterative examination and improvement of processes to address challenges of breast cancer care planning, team-based delivery and patient engagement. Results: Case studies in the evolution of patient navigation research programs show how identified gaps in care were remedied pragmatically in the course of each study. We show how patient navigation implementation efforts have been aided with evolving models incorporating the local implementation context, characteristics of program implementers, and structural, macro-level factors involving care delivery systems and public policy. Results highlight approaches for supporting organizational learning to enhance implementation and sustainability of navigation interventions; for furthering task clarification and coordination to optimize integration of patient navigation into cancer care delivery settings; and for tackling the impact of existing local, state, and national policy initiatives on patient navigation. Conclusions: Reducing breast cancer burden, especially among underserved populations, warrants adaptive, ongoing improvement of patient navigation models. Through iterative intervention development, evaluation, and refinement, patient navigation can move beyond serving as a temporary bandage for health systems fragmentation and toward an essential role in systems change for optimizing cancer care delivery. Citation Format: Melissa A. Simon, Laura S. Tom, Julia R. Trosman, Christine B. Weldon, Catherine A. O'Brian, Marcie C. Kirschner, XinQi Dong. The evolution of patient navigation research models to reduce breast cancer disparities: Case studies of patient navigation dissemination and implementation in Chicago [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1637.