The current study examined the relationship between depression and uncertainty within the stress-diathesis model. Depression is a mental health disorder that is wide spread within our society. However, few causes of this disease have been able to be identified. Studies in uncertainty have shown that it is a major stressor in day-to-day life. Previous research has shown that individuals with high levels of uncertainty show higher levels of depression. The stress-diathesis model, a model originally developed to explain differences in development of schizophrenia, provides a theoretically meaningful way to combine these two concepts. The model states that a person who is likely to develop a disease has an internal mechanism, a diathesis, that will be triggered upon presentation of a stressor. This study tested the idea that uncertainty can be used as a stressor to activate diathesis within an individual, aiding in the prediction of depression. In total, 163 participants were randomly assigned one of three conditions, an uncertainty threat, an affirmation condition, and a control condition. Participants were given pre and post independent variable measures of depression and anxiety. Findings suggest that uncertainty activated negative emotions differentially within the participants, resulting in higher levels of negative affects after the uncertainty threat, especially for participants who already scored relatively higher on depression indicators. These results hint at a possible understanding of why depression rates and diagnosis rates of mental health issues rise during economic downturn and other times of strong uncertainty.