In this article, we provide a fresh perspective on the developmental origins of neuroticism--a dimension of temperament marked by elevated stress reactivity resulting in the frequent experience of negative emotions. This negative affectivity is accompanied by a pervasive perception that the world is a dangerous and threatening place, along with beliefs about one's inability to manage or cope with challenging events. Historically, neuroticism has been viewed as a stable, genetically based trait. However, recent understanding of ongoing gene-environment interactions that occur throughout the life span suggests there may be a more complex and dynamic etiology. Thus, the purpose of this article is to offer a theory for understanding the development of neuroticism that integrates genetic, neurobiological, and environmental contributions to this trait. Given the strong correlation between neuroticism and the development of negative health outcomes--most notably, the full range of anxiety and mood disorders--an enhanced understanding of how neuroticism originates has implications for the treatment and prevention of a broad range of pathologies and, perhaps, even for the prevention of neuroticism itself.