The birth defect known as optic nerve hypoplasia (ONH), characterized by an underdeveloped optic nerve, has emerged as the single leading cause of childhood blindness and visual impairment in the United States and Europe. Since the first description of ONH, research has made tremendous progress in understanding the clinical significance of ONH. It is now clear that ONH is a pervasive disease of child neurodevelopment associated with overall miswiring of the brain that results in visual impairment and profound systemic and functional morbidity. A review of the disease summarizes the clinical profile associated with ONH. The prenatal determinants of ONH are largely unknown owing to a lack of systematic research in a large sample of cases. A review of literature identified a broad spectrum of suggested risk factors born primarily out of anecdotal reports and highly selective case samples. This dissertation includes two analyses aimed at clarifying the prenatal risk profile. The first is a retrospective analysis of the prenatal history in a large clinical cohort of cases of ONH using a maternal questionnaire to systematically assess the exposures and complications during gestation. The findings refuted the majority of previously suggested risk factors and identified new potentially significant prenatal characteristics that suggest nutrition and weight gain may play a role in the development of ONH. The second analyses used a national on-line registry of cases of ONH to investigate a secondary component to ONH – the presence of disease clusters. The findings provide evidence of spatial clusters in many areas of the United States. The findings also identified geographic areas with a high density of cases that may be used for future investigations.; As a result of these two analyses, a study is proposed that will further investigate among other things the new potentially significant prenatal characteristics using a study sample from a geographically confined area with a high concentration of cases.