Background: Recent reports suggest that less than 20% of cancer care is based upon level I evidence. As a result, the majority of cancer care tends to be ad-hoc. Furthermore, deviations from established standards-of-care are associated with worse clinical outcomes. Systematic and evidence-based approaches to cancer care are widely regarded as an effective way of improving quality and value in oncology, yet their implementation remains broadly circumspect. In our multicenter radiation medicine department, we developed clinical practice guidelines (CPGs) that encourage consistent care in order to minimize variations in patient treatment, outcome, and experience. We hypothesized that CPGs would also improve efficiency, performance, and cost. Methods: We developed a system for prioritizing value in radiation oncology (Smarter Radiation Oncology) comprising three pillars – quality, evidence-based care, and patient experience. We created 87 unique, evidence-based and consensus-driven electronic CPGs that apply to the majority of patients undergoing radiation therapy in our department. Each CPG delineates an evidence-based treatment approach for a specific cancer site and stage, as well as many technical components such as simulation, treatment planning, quality assurance, clinical care requirements and survivorship. Results: Overall compliance to CPGs was >88%. Six-sigma Z-scores indicated improvement in efficiency and compliance. Treatment delays decreased and patients reported more favorable ratings on a variety of measures, including likelihood to recommend, wait times, understanding of treatment, and physician sensitivity. For breast and prostate cancer, adherence to CPG treatment resulted in 20% and 15% average lower costs than standard, non-CPG treatment. Conclusions: We demonstrate that consensus- and evidence-based CPGs can be successfully implemented in a multicenter department, with high adherence rates. CPGs improve safety and reduce costs by minimizing variation and deviations from standards-of-care. In an era of rising cancer spending, CPGs can be expanded beyond radiation oncology to the entire oncologic care process, thereby improving value for all cancer patients.