Diarrheal disease is still a major cause of mortality and morbidity worldwide; thus a large body of research has been produced describing its risks. We review more than four decades of literature on diarrheal disease epidemiology. These studies detail a progression in the conceptual understanding of transmission of enteric pathogens and demonstrate that diarrheal disease is caused by many interdependent pathways. However, arguments by diarrheal disease researchers in favor of attending to interaction and interdependencies have only recently yielded more formal systems-level approaches. Therefore, interdependence has not yet been highlighted in significant new research initiatives or policy decisions. We argue for a systems-level framework that will contextualize transmission and inform prevention and control efforts so that they can integrate transmission pathways. These systems approaches should be employed to account for community effects (i.e., interactions among individuals and/or households).