Self-regulation seems crucial to understanding how employees perform under stress because employees must regulate their thoughts, feelings, and behavior to deal effectively with work stress. Integrating regulatory focus theory and the challenge–hindrance stressor framework, we theorized that the effects of regulatory focus on job performance would vary as a function of the level of stress employees experience. Specifically, we contend that employees are more efficacious and motivated (and thus perform better) when they have established goal and coping strategies that allow them to cope with the stress they face; those lacking in these strategies are likely to find the stress overwhelming and taxing (and perform worse). Using multisource data of 160 salespersons, we investigated this relationship with two measures of job performance. We found that challenge stress moderates the relationship between promotion focus and job performance: When challenge stress is high, promotion focus is positively related to job performance; when low, promotion focus is negatively or not significantly related to job performance. We also found that hindrance stress moderates the relationship between prevention focus and job performance: When hindrance stress is low, prevention focus is negatively related to job performance, but when high, prevention focus is positively related to job performance. Moreover, we find some support for three-way interactions suggesting that using mismatched goal and coping strategies is especially harmful. Our results explain performance differences in high-stress situations and highlight the important role of self-regulation when employees are in stressful conditions.