A growing body of research is identifying the molecular and genetic correlates of psychopathology and holds tremendous promise in suggesting the biologic mechanisms that may explain emergent posttraumatic stress disorder (PTSD) phenotypes. Another body of research has begun to consider how elements of the social context may influence the risk of PTSD. It is likely that the social context and molecular/genetic factors jointly determine the risk of PTSD and as such scientific inquiry that considers the interrelationship of these factors stands to advance the field. However, there are particular conceptual and methodologic challenges to conducting and designing studies that adequately assess both the social context and the biologic determinants of PTSD. Much of the current research exploring the biology of PTSD is conducted with highly selective samples that were recruited on the basis of strict phenotypic or medical history criteria. In contrast, population-based sampling represents an opportunity to obtain heterogeneous samples that better represent the population distribution of relevant molecular, genotypic, and phenotypic parameters of interest. These sampling strategies also allow researchers to consider the role of the social context and in turn, how the social context influences the molecular determinants of PTSD. An example of our own work illustrates the feasibility of the population-based sampling approach.