A growing literature investigates associations between neighborhood social environments and coronary heart disease (CHD). After reviewing the literature, we present a theoretical model of the mechanisms through which geographic life environments may influence CHD, focusing particularly on the social-interactional environment. We suggest that, in addition to the common notions of social cohesion or fragmentation and social disorder, eco-epidemiologists should consider neighborhood identities and stigmatization processes. We posit that neighborhood social interactions affect the wide set of affective, cognitive, and relational experiences individuals have in their neighborhoods, which in turn influence the psycho-cognitive antecedents of behavior and in the end shape health behavior. Finally, we discuss key methodological challenges relevant to the advent of a new generation of neighborhood studies, including the operational definition of neighborhoods, non-residential environments, ecometric measurement, model specification strategies, mediational models, selection processes and notions of empirical/structural confounding, and the relevance of observational versus interventional studies.