Community-level policy, systems, and environmental (PSE) change strategies may offer an economical and sustainable approach to chronic disease prevention. The rapidly growing number of untested but promising PSE strategies currently underway offers an exciting opportunity to establish practice-based evidence for this approach. This article presents lessons learned from an evaluation of a community-based PSE initiative targeting stroke and cardiovascular disease prevention in the Mississippi Delta. Its purpose is to describe one approach to evaluating this type of PSE initiative, to stimulate discussion about best practices for evaluating PSE strategies, and to inform future evaluation and research efforts to expand practice-based evidence. The evaluation used a descriptive mixed-methods design and focused on the second year of a multisectoral, multiyear initiative. Cross-sectional data were collected in the summer and fall of 2010 using four data collection instruments: a grantee interview guide (n = 32), a health council member survey (n = 256), an organizational survey (n = 60), and a grantee progress report (n = 26). Fifty-eight PSE changes were assessed across five sectors: health, faith, education, worksite, and community/city government. PSE strategies aligned with increased access to physical activity opportunities, healthy food and beverage options, quality health care, and reduced exposure to tobacco. Results showed that grantees were successful in completing a series of steps toward PSE change and that sector-specific initiatives resulted in a range of PSE changes that were completed or in progress. Considerations for designing evaluations of community-based PSE initiatives are discussed.