The National Cancer Institute’s (NCI) Implementation Science in Cancer Control Centers (ISC3) Network represents a large-scale initiative to create an infrastructure to support and enable the efficient, effective, and equitable translation of approaches and evidence-based treatments to reduce cancer risk and improve outcomes. This Cancer Moonshot funded ISC3 Network consists of seven P50 Centers that support and advance the rapid development, testing, and refinement of innovative approaches to implement a range of evidence-based cancer control interventions. The Centers were designed to have research-practice partnerships at their core, and to create the opportunity for a series of pilot studies that could explore new and sometimes risky ideas and embed in their infrastructure a two-way engagement and collaboration essential to stimulating lasting change. ISC3 also seeks to enhance capacity of researchers, practitioners and communities to apply implementation science approaches, methods, and measures. The Organizing Framework that guides the work of ISC3 highlights a collective set of three core areas of collaboration within and among Centers, including: (1) assess and incorporate dynamic, multilevel context; (2) develop and conduct rapid and responsive pilot and methods studies; and (3) build capacity for knowledge development and exchange. Core operating principles that under-gird the framework include open collaboration, consideration of the dynamic context and engagement of multiple implementation partners to advance pragmatic methods, advancement of health equity, and facilitation of leadership and capacity building across Implementation Science and cancer control.