A growing body of evidence has highlighted an association between a lack of access to nutritious, affordable food (e.g., through full-service grocery stores [FSGs]), poor diet, and increased risk for obesity. In response, there has been growing interest among policy makers in encouraging the siting of supermarkets in "food deserts," that is, low-income geographic areas with low access to healthy food options. However, there is limited research to evaluate the impact of such efforts, and most studies to date have been cross-sectional. The Pittsburgh Hill/Homewood Research on Eating, Shopping, and Health (PHRESH) is a longitudinal quasi-experimental study of a dramatic change (i.e., a new FSG) in the food landscape of a low-income, predominantly Black neighborhood. The study is following a stratified random sample of households (n = 1,372), and all food venues (n = 60) in both intervention and control neighborhoods, and the most frequently reported food shopping venues outside both neighborhoods. This article describes the study design and community-based methodology, which focused simultaneously on the conduct of scientifically rigorous research and the development and maintenance of trust and buy-in from the involved neighborhoods. Early results have begun to define markers for success in creating a natural experiment, including strong community engagement. Baseline data show that the vast majority of residents already shop at a FSG and do not shop at the nearest one. Follow-up data collection will help determine whether and how a new FSG may change behaviors and may point to the need for additional interventions beyond new FSGs alone.