Defining neighborhoods for health research continues to be challenging. This chapter discusses different methods to operationalize neighborhood boundaries, including self-report, administrative definitions, geographic information system buffers and activity spaces, including global positioning system (GPS)–defined activity spaces. It discusses the strengths and limitations of each method of examining neighborhood boundaries (e.g., spatial misclassification, technical difficulties, assumptions). Readers are provided with examples of neighborhood definitions frequently applied in the epidemiology and population health literature. In addition, the chapter provides a rigorous overview of theories for selecting neighborhood definitions, including spatial polygamy theory for GPS-defined activity space neighborhoods.